Epistemic_Statements  

CORD-19:f212d6366a45726107a30bde1f4615c28cb5ce22 JSONTXT 8 Projects

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Id Subject Object Predicate Lexical cue
T1 681-791 Epistemic_statement denotes They are very flexible, but some may undergo disorder to order transitions in the presence of natural ligands.
T2 1027-1123 Epistemic_statement denotes When lacking proper control, they have multiple roles in pathogenesis of various human diseases.
T3 1124-1277 Epistemic_statement denotes Gaining structural and functional information about these proteins is a challenge, since they do not typically "freeze" while their "pictures are taken."
T4 1278-1475 Epistemic_statement denotes However, despite or perhaps because of the experimental challenges, these fuzzy objects with fuzzy structures and fuzzy functions are among the most interesting targets for modern protein research.
T5 1848-2348 Epistemic_statement denotes 1 The major goal of that article was to bring an intriguing protein family of natively unfolded proteins (which are recognized now to constitute a subset of a very broad class of intrinsically disordered proteins, IDPs) out of shadow, to emphasize their lack of ordered structure under physiological conditions (at least ordered structure that could be detected by traditional low resolution techniques), to systemize their major structural properties, and to highlight their biological significance.
T6 2934-3151 Epistemic_statement denotes These observations provoked an idea that these biologically important proteins with little or no ordered structure have to wait to become more folded (and functional) as a result of binding to their specific partners.
T7 3152-3446 Epistemic_statement denotes In other words, for these proteins, "biology," that is, the ability to have biological functions, seemed to wait for "physics" which is manifested in their ability to undergo binding-induced folding (at least partial), which is necessary to bring the functional state of these proteins to life.
T8 3447-3812 Epistemic_statement denotes 1 At the beginning, the idea that structure-less proteins can be biologically active was taken as a complete heresy by many researchers, since it was absolutely alien to then dominated structure-function paradigm which represented a foundation of the long-standing belief that the specific functionality of a given protein is determined by its unique 3-D structure.
T9 3813-3989 Epistemic_statement denotes This structure-function paradigm that describes reasonably well the catalytic behavior of enzymes was based on the "lock-and-key" hypothesis formulated in 1894 by Emil Fischer.
T10 4268-4492 Epistemic_statement denotes These many crystal structures reinforced a static view of functional protein, where a rigid active site of an enzyme can be viewed as a sturdy lock that provides an exact fit to only one key, a specific and unique substrate.
T11 4493-4647 Epistemic_statement denotes 4 Despite numerous limitations, this lock-and-key model was an extremely fruitful concept that was responsible for the creation of modern protein science.
T12 4882-5116 Epistemic_statement denotes 1 Obviously, the consideration of a protein as a rigid crystal-like entity is an oversimplification, since even the most stable and well-folded proteins are dynamic systems that possess different degrees of conformational flexibility.
T13 5117-5362 Epistemic_statement denotes This is because of the simple fact that so-called conformational forces, that is, forces stabilizing the secondary structure of a protein and its tertiary fold, are weak and can be broken even at ambient temperatures due to thermal fluctuations.
T14 5363-5575 Epistemic_statement denotes 4 The breaking of these weak interactions releases the groups that were involved in these interactions and gives them the possibility to be involved in the formation of new weak interactions of comparable energy.
T15 5911-6057 Epistemic_statement denotes 6 Furthermore, one should keep in mind that not all proteins structures which are deposited to PDB are structured throughout their entire lengths.
T16 6724-7085 Epistemic_statement denotes 4 Therefore, there is another class of functional proteins and protein regions that contain smaller or larger highly dynamic fragments, and some proteins are even characterized by a complete or almost complete lack of ordered structure under physiological conditions (at least in vitro) which appears to be a critical aspect of these proteins' function in vivo.
T17 7440-7597 Epistemic_statement denotes These proteins were independently discovered one-by-one over a long period of time and therefore they were considered as rare exceptions to the general rule.
T18 7598-7840 Epistemic_statement denotes Although the phenomenon of biological functionality without stable structure was repeatedly observed, for a long time it was unnoticed by a wide audience because the authors frequently invented new terms to describe their protein of interest.
T19 8740-9015 Epistemic_statement denotes 16 Although protein intrinsic disorder is considered now as an established concept and PubMed contains hundreds and hundreds of papers talking about different aspects of IDPs/IDPRs, the route to recognizing these proteins as a novel functional entity was complex and lengthy.
T20 9454-9662 Epistemic_statement denotes 12 However, time showed that the concept of protein intrinsic disorder was a useful invention and could be considered as a universal lock-pick that helps in solving many of the seemingly unsolvable Figure 1 .
T21 9768-9873 Epistemic_statement denotes Some major directions based on the consideration of protein function as lock-and-key mechanism are shown.
T22 10042-10363 Epistemic_statement denotes In essence, introduction of this concept can be considered as a scientific revolution that, according to Kuhn, 5 "occurs when scientists encounter anomalies that cannot be explained by the universally accepted paradigm within which scientific progress has thereto been made" (http://en.wikipedia.org/wiki/Paradigm_shift).
T23 10401-10564 Epistemic_statement denotes One could say that this idea gave a new boost to the development of the protein science, generating a wide array of principally novel research directions [see Fig.
T24 10573-11483 Epistemic_statement denotes The goals of this review are: (i) to outline some recent advances in the field of IDPs/IDPRs; (ii) to illustrate the usefulness of intrinsic disorder for protein function; (iii) to show that intrinsic disorder can affect different levels of protein structural organization; (iv) to indicate intimate involvement of intrinsic disorder in pathogenesis of various maladies; (v) to emphasize the exceptional structural heterogeneity of IDPs/IDPRs and to show that IDPs are definitely much more structurally complex than random coillike polypeptides; (vi) to accentuate that although this structural heterogeneity is very important for protein functionality, it represents a crucial hurdle for structural characterization of IDPs; (vii) to stress that new experimental and computational approaches and new theories and models are crucially needed for future progression of this field and protein science in general.
T25 11484-11723 Epistemic_statement denotes These and other points highlight the current state of the field, where further advances in understanding of the "biology" of IDPs still waits for "physics," with "physics" now being new theories, instrumentation, and analytical approaches.
T26 12315-12620 Epistemic_statement denotes 12 Therefore, compact proteins and extended IDPs can be distinguished based only on their net charges and hydropathies using a simple charge-hydropathy (CH) plot, where the IDPs are specifically localized within a specific region of CH phase space and are reliably separated from compact ordered proteins.
T27 13313-13568 Epistemic_statement denotes 34 and more than 6000 composition-based attributes (e.g., all possible combinations having one to four amino acids in the group) 36 it has been concluded that ordered and disordered proteins and regions can be discriminated using many of these attributes.
T28 13863-14317 Epistemic_statement denotes 30 The fact that the sequences of ordered and disordered proteins and regions are noticeably different suggested that IDPs clearly constitute a separate entity inside the protein kingdom, that these proteins can be reliably predicted using various computational tools, [37] [38] [39] [40] [41] [42] and structurally, that IDPs should be very different from ordered globular proteins since peculiarities of amino acid sequence determine protein structure.
T29 14653-14921 Epistemic_statement denotes 1 It was also pointed out that this list would probably be doubled if shorter polypeptides 30-50 residues long were included, 1 and that these 100 experimentally validated natively unfolded have at least 250 homologues, which are also expected to be natively unfolded.
T30 14922-15169 Epistemic_statement denotes 1, 12 It happened that these "large" numbers (which actually were large enough to make a crucial point that biologically active structure-less proteins represent the new rule and not mere rare exceptions) constitute just a small tip of an iceberg.
T31 15170-15348 Epistemic_statement denotes In fact, using computational tools developed for sequence-based intrinsic disorder prediction the wide spread of IDPs and hybrid proteins containing IDPRs was convincingly shown.
T32 16044-16440 Epistemic_statement denotes 44, [48] [49] [50] [51] [52] This conclusion is in line with the results of a comprehensive bioinformatics investigation of the disorder distribution in almost 3500 proteomes from viruses and three kingdoms of life, results of which are shown in Figure 2 as the correlation between the intrinsic disorder content and proteome size for 3484 species from viruses, archaea, bacteria, and eukaryotes.
T33 16441-16762 Epistemic_statement denotes 46 Surprisingly, Figure 2 shows that there is a well-defined gap between the prokaryotes and eukaryotes in the plot of fraction of disordered residues on proteome size, where almost all eukaryotes have 32% or more disordered residues, whereas the majority of the prokaryotic species have 27% or fewer disordered residues.
T34 16763-17054 Epistemic_statement denotes 46 Therefore, it looks like the fraction of 30% disordered residues serves as a boundary between the prokaryotes and eukaryotes and reflects the existence of a complex step-wise correlation between the increase in the organism complexity and the increase in the amount of intrinsic disorder.
T35 17055-17268 Epistemic_statement denotes A gap in the plot of fraction of disordered residues on proteome size parallels a morphological gap between prokaryotic and eukaryotic cells which contain many complex innovations that seemingly arose all at once.
T36 17269-17530 Epistemic_statement denotes In other words, this sharp jump in the disorder content in proteomes associated with the transition from prokaryotic to eukaryotic cells suggests that the increase in the morphological complexity of the cell paralleled the increased usage of intrinsic disorder.
T37 17531-17940 Epistemic_statement denotes 46 The variability of disorder content in unicellular eukaryotes and rather weak correlation between disorder status and organism complexity (measured as the number of different cell types) is likely related to the wide variability of their habitats, with especially high levels of disorder being found in parasitic host-changing protozoa, the environment of which changes dramatically during their life-span.
T38 17941-18227 Epistemic_statement denotes 53 The further support for this hypothesis came from the fact that the intrinsic disorder content in multicellular eukaryotes (which are characterized by more stable and less variable environment of individual cells) was noticeably less variable than that in the unicellular eukaryotes.
T39 18513-18635 Epistemic_statement denotes These observations seem to indicate that the sequence space of IDPs/IDPRs should be simpler than that of ordered proteins.
T40 18636-18854 Epistemic_statement denotes However, the reality is more complex than conventional wisdom might suggest, and the sequence space attainable by simple IDPs/IDPRs is more diversified than that of the structurally more sophisticated ordered proteins.
T41 18855-19009 Epistemic_statement denotes In fact, a 100 residue-long protein in which any of the normally occurring 20 amino acids can be found has a sequence space of 20 100 (10 130 ) sequences.
T42 19010-19092 Epistemic_statement denotes 54 Obviously, not all random amino acid sequences can fold into unique structures.
T43 19274-19544 Epistemic_statement denotes For decades, the actual size of "foldable" sequence space continues to be unsolved mystery despite a large body of theoretical, biochemical, and computational work that aims to unravel the relationship between a protein's primary sequence and its resulting 3D structure.
T44 19545-19827 Epistemic_statement denotes 55 However, the actual number of different amino acid residues in a given foldable sequence can be dramatically reduced, 54 since all twenty residues are not necessary for protein folding and the actual physicochemical identity of most of the amino acids in a protein is irrelevant.
T45 19828-20132 Epistemic_statement denotes [56] [57] [58] [59] [60] [61] [62] [63] In other words, folding alphabet can be noticeably reduced, 55, 64 and amino acids can be clustered based on some shared features such as homolog substitution frequency, 65 local structural environments, 66 or peculiarities of the tertiary structural environments.
T46 20236-20370 Epistemic_statement denotes Correlation between the intrinsic disorder content and proteome size for 3484 species from viruses, archaea, bacteria, and eukaryotes.
T47 22270-22563 Epistemic_statement denotes 74, 75 All this suggests that the sequence space of IDPs (at least those which either do not fold at all or do not completely fold at binding) is noticeably greater than the "foldable" sequence space due to the removal of restrictions posed by the need to gain ordered structure spontaneously.
T48 22823-22920 Epistemic_statement denotes Also, the existence of a noticeable sequencestructure heterogeneity of IDPs should be emphasized.
T49 22921-23176 Epistemic_statement denotes 68 Since the unique 3D-structure of an ordered single-domain protein is defined by the interplay between all (or almost all) of its residues, one could expect that the structure-coding potential is homogeneously distributed within its amino acid sequence.
T50 23177-23351 Epistemic_statement denotes On the other hand, a sequence of an IDP/IDPR contains multiple, relatively short functional elements and therefore represents a very complex structural and functional mosaic.
T51 23769-23771 Epistemic_statement denotes 77
T52 23772-24010 Epistemic_statement denotes One of the crucial consequences of an extended sequence space and non-homogeneous distribution of foldability (or the structure-coding potential) within amino acid sequences of IDPs and IDPRs is their astonishing structural heterogeneity.
T53 24011-24187 Epistemic_statement denotes In fact, a typical IDP/IDPR contains a multitude of elements coding for potentially foldable, partially foldable, differently foldable, or not foldable at all protein segments.
T54 24548-24768 Epistemic_statement denotes 68 Another level of structural heterogeneity is determined by the fact that many proteins are hybrids of ordered and disordered domains and regions, and this mosaic structural organization is crucial for their functions.
T55 25809-25985 Epistemic_statement denotes However, already in some early studies, it was indicated that IDPs/IDRs could be crudely grouped into two major structural classes, proteins with compact and extended disorder.
T56 25986-26312 Epistemic_statement denotes 1, 4, 12, 13, 73 Based on these observations, the protein functionality was ascribed to at least three major protein conformational states, ordered, molten globular, and coil-like, 13, 79 indicating that functional IDPs can be less or more compact and possess smaller or larger amount of flexible secondary/tertiary structure.
T57 26560-26829 Epistemic_statement denotes 1 Currently available data suggest that intrinsic disorder possesses multiple flavors, can have multiple faces, and can affect different levels of protein structural organization, where whole proteins, or various protein regions can be disordered to a different degree.
T58 27211-27577 Epistemic_statement denotes Other functional proteins may contain limited number of disordered regions (a grass-on-the rock scenario), or have significant amount of disordered regions (a llama/camel hair scenario), or be molten globule-like (a greasy ball scenario), or behave as pre-molten globules (a spaghetti-and-meatballs/sausage scenario), or be mostly unstructured (a hairball scenario).
T59 27578-27743 Epistemic_statement denotes Notably, in this representation, there is no boundary between ordered proteins and IDPs, and, the structure-disorder space of a protein is considered as a continuum.
T60 27875-28049 Epistemic_statement denotes In fact, a protein molecule is an inherently flexible entity and the presence of this flexibility (even for the most ordered proteins) is crucial for its biological activity.
T61 28372-28594 Epistemic_statement denotes would find biophysical properties of functional IDPs/IDPRs to be rather unusual since these highly dynamic proteins do not follow the well-accepted wisdom that a protein has to be well-folded to be biologically functional.
T62 28595-28742 Epistemic_statement denotes However, the unusualness is a subjective feature, and from the viewpoint of polymer physics the extended IDPs/IDPRs possess the expected behavior .
T63 29071-29258 Epistemic_statement denotes Bottom half: A continuous emission spectrum representing the fact that functional proteins can extend from fully ordered to completely structure-less proteins, with everything in between.
T64 29259-29454 Epistemic_statement denotes Intrinsic disorder can have multiple faces, can affect different levels of protein structural organization, and whole proteins, or various protein regions can be disordered to a different degree.
T65 30199-30385 Epistemic_statement denotes Therefore, one definitely should keep in mind that the "unusual" biophysics of extended IDPs/IDPRs has its roots in the usual polymer physics of highly charged and flexible polypeptides.
T66 30386-30565 Epistemic_statement denotes Each protein is believed to be a unique entity that has quite unique primary sequence which governs its 3D structure (or lack thereof) and ensures specific biological function(s).
T67 30682-30851 Epistemic_statement denotes However, natural polypeptides have originated as random copolymers of amino acids, which were adjusted or "selected" over evolution based on their functional capacities.
T68 30852-31166 Epistemic_statement denotes 56, 81 Despite their differences in primary amino acid sequences, protein molecules in a number of conformational states behave as polymer homologues, suggesting that the volume interactions can be considered as a major driving force responsible for the formation of equilibrium structures or structural ensembles.
T69 31167-31470 Epistemic_statement denotes 82 For example, ordered globular proteins and molten globules (both as folding intermediates of globular proteins or as examples of collapsed IDPs) exhibit key properties of polymer globules, where the fluctuations of the molecular density are expected to be much less than the molecular density itself.
T70 31695-31936 Epistemic_statement denotes In fact, even high concentrations of strong denaturants (e.g., urea and GdmCl) are very likely to be bad solvents for protein chains, resulting in the preservation of extensive residual structure even under these harsh denaturing conditions.
T71 31937-32288 Epistemic_statement denotes 82 Based on these and related observations, and taking into account the fact that many IDPs/IDPRs are characterized by significant amino acid composition biases, the overall polymeric behavior of these proteins and regions can be mimicked reasonably well by the behavior of low-complexity polypeptides (e.g., homopolypeptide and block copolypeptides).
T72 33152-33439 Epistemic_statement denotes 89 Overall, the increase in the hydrodynamic dimensions of a polypeptide chain with increase in its net charge per residue can be attributed to the increase in the intramolecular electrostatic repulsions between similarly charged sidechains and the favorable solvation of these moieties.
T73 34122-34312 Epistemic_statement denotes Furthermore, if such IDPs/ IDPRs possess polyampholytic nature, their globular state could be additionally stabilized by electrostatic interactions between the oppositely charged sidechains.
T74 34498-34669 Epistemic_statement denotes Such intrinsically disordered protein can form collapsed structures stabilized mostly by multiple electrostatic interactions between solvated side-chains of opposite sign.
T75 34986-35436 Epistemic_statement denotes 90 For example, based on the analysis of the conformational equilibrium of coarse-grained polypeptides as a function of sequence hydrophobicity, charge, and length it has been concluded that the variations in sequence hydrophobicity and charge define a coil-to-globule transition comparable to that seeing in the empirical CH-plot, 12, 91 suggesting that a minimal, polymer physics-based model can capture the elements of global protein conformation.
T76 35437-35628 Epistemic_statement denotes 92 IDPs/IDPRs with very high net charges are expected to be more extended and behave more similar to random coils (i.e., similar to conformations adopted by proteins in the denaturant GdmCl).
T77 35629-35827 Epistemic_statement denotes The analysis of the GdmCl-induced expansion of the unfolded states suggested that protein charge density plays a crucial role in defining the hydrodynamic behavior of the unfolded polypeptide chain.
T78 35828-35956 Epistemic_statement denotes 90 Here, highly charged proteins can exhibit a prominent expansion at low ionic strength that correlates with their net charges.
T79 35957-36130 Epistemic_statement denotes 90 It has been also hypothesized that the pronounced effect of charges on the dimensions of unfolded proteins might have important implications for their cellular functions.
T80 37019-37304 Epistemic_statement denotes These observations suggested that different types of FGdomains with different aggregation propensities provide molecular basis for two different gating mechanisms operating at the nuclear pore complex at distinct locations; one acting as a hydrogel, and the other as an entropic brush.
T81 37305-37495 Epistemic_statement denotes 94 Therefore, the abundance and peculiarities of the charged residues distribution within the protein sequences might determine physical and biological properties of extended IDPs and IDPRs.
T82 37496-37636 Epistemic_statement denotes Also, simple polymer physics-based reasoning can give reasonably well-justified explanation of the conformational behavior of extended IDPs.
T83 38885-39099 Epistemic_statement denotes 95 Every Disordered Protein is Disordered in its Own Way Data accumulated so far indicate that intrinsic disorder exists at multiple structural levels and might differently affect different regions/domains of IDPs.
T84 39277-39554 Epistemic_statement denotes Furthermore, since intrinsic disorder is crucial for many biological functions and therefore must prevail in different environments, the amino acid sequences and compositions of IDPs and IDPRs are specifically shaped by the peculiarities of their global and local environments.
T85 39762-39994 Epistemic_statement denotes This hypothesis has far-reaching consequences since it implies that a general disorder predictor has limited accuracy and cannot predict with equally high accuracy disorder status of all protein sequences due to their heterogeneity.
T86 39995-40129 Epistemic_statement denotes It also implies that some environmental factors definitely should be taken into account when assessing intrinsic disorder in proteins.
T87 41089-41363 Epistemic_statement denotes For example, similar to typical water soluble proteins, the TM regions of membrane proteins are often highly structured, containing a-helices 109 or b-structure, 110 which are especially likely to occur due to the low dielectric constant values within the membrane bilayers.
T88 41822-41975 Epistemic_statement denotes Therefore, the IDPRs found in integral membrane proteins would be expected to be generally localized within the regions external to the membrane bilayer.
T89 42647-42876 Epistemic_statement denotes Therefore, the use of specific amino acid signatures of IDPRs found in TM helical bundles and b-barrels can potentially lead to significantly more accurate disorder predictions for these two classes of integral membrane proteins.
T90 43316-43633 Epistemic_statement denotes 46, 51 Similar to TM proteins, the estimation of intrinsic disorder in the extremophilic proteins of the microorganisms surviving under hypersaline conditions using predictors developed for the "normal" non-halophilic proteins existing under the normal physiological conditions of 100-150 mM NaCl may not be accurate.
T91 44428-44488 Epistemic_statement denotes [118] [119] [120] [121] [122] [123] [124] [125] [126] [127]
T92 44489-44639 Epistemic_statement denotes Finally, peculiarities of disorder distributions in viral proteins can be used to further support the importance of considering environmental factors.
T93 44970-45446 Epistemic_statement denotes 46 The high predicted intrinsic disorder content in viruses has multiple functional implications, where some IDPRs are used in the functioning of viral proteins and help viruses to highjack various pathways of the host cells, others likely have evolved to help viruses accommodate to their hostile habitats, and still others evolved to help viruses in managing their economic usage of genetic material via alternative splicing, overlapping genes, and anti-sense transcription.
T94 45817-45821 Epistemic_statement denotes 129
T95 45822-45910 Epistemic_statement denotes Functional protein clouds: Major functional advantages of being intrinsically disordered
T96 45911-46080 Epistemic_statement denotes The high natural abundance of IDPds/IDPRs and their specific structural features indicate that these proteins and regions might carry out important biological functions.
T97 46081-46527 Epistemic_statement denotes This hypothesis has been confirmed by several comprehensive studies, 1, [11] [12] [13] [14] [71] [72] [73] 78, [130] [131] [132] [133] [134] which revealed that these structure-less members of the protein kingdom are abundantly involved in numerous biological processes, where they are frequently found to play different roles in regulation of the functions of their binding partners and in promotion of the assembly of supra-molecular complexes.
T98 46884-46982 Epistemic_statement denotes 4, 10, 11, 13, 32, 71, 72, 77, 78, 131, 132, 134, 141, 142, 150, 151 Some of these advantages are:
T99 46983-49415 Epistemic_statement denotes 1 Increased speed of interaction due to greater capture radius and the ability to spatially search through interaction space; 2 Increased interaction (surface) area per residue; 3 Strengthened encounter complex allows for less stringent spatial orientation requirements; 4 Efficient regulation via rapid degradation; 5 The ability to be involved in one-to-many binding, where a single disordered region binds to several structurally diverse partners; 6 The ability to be involved in many-to-one binding, where many distinct (structured) proteins may bind a single disordered region; 7 The ability to overcome steric restrictions, enabling larger interaction surfaces in protein-protein and protein-ligand complexes than those obtained with rigid partners; 8 The ability to fold upon binding (completely or partially); 9 The ability of some IDPs/IDPRs to form very stable intertwined complexes; 10 The ability of some IDPs/IDPRs to stay substantially disordered in bound state; 11 Binding fuzziness, where different binding mechanisms (e.g., via stabilizing the binding-competent secondary structure elements within the contacting region, or by establishing the longrange electrostatic interactions, or being involved in transient physical contacts with the partner, or even without any apparent ordering) can be employed to accommodate peculiarities of interaction with various partners; 12 Binding plasticity, where an IDPR folds to specific bound conformations (which can be very different) according to the template provided by binding partners; 13 High accessibility of sites targeted for posttranslational modifications (PTMs); 14 Efficient structural and functional regulation via PTMs such as phosphorylation, acetylation, lipidation, ubiquitination, sumoylation, and so forth, allowing for a simple means of modulation of their biological functions; 15 Efficient functional control via regulatory proteolytic attack sites of which are frequently associated with IDPRs; 16 Ease of regulation/redirection and production of otherwise diverse forms by alternative splicing (given the existence of multiple functions in a single disordered protein, and given that each functional element is typically relatively short, alternative splicing could readily generate a set of protein isoforms with a highly diverse set of regulatory elements 152 ); 17 The possibility of overlapping binding sites due to extended linear conformation;
T100 49416-49571 Epistemic_statement denotes 18 Decoupled binding affinity and specificity, where, due to the induced folding, IDP/IDPR can be involved in the formation of specific but weak complexes.
T101 49572-49772 Epistemic_statement denotes In other words, IDP/IDPR might possess high specificity for given partners combined with high k on and k off rates that enable rapid association with the partner without an excessive binding strength.
T102 50101-50587 Epistemic_statement denotes The latter ones can evolve into sophisticated and complex interaction centers (scaffolds) that can be easily tailored to the needs of divergent organisms; 20 Flexibility that allows masking (or not) of interaction sites or that allows interaction between bound partners; 21 The ability to be involved in the cascade interactions, where IDP binding to the first partner induces partial folding generating a new binding site suitable for interaction with the second partner, and so forth.
T103 51407-51655 Epistemic_statement denotes 71, 72 Later, a rich spectrum of biological functions associated with IDPs/IDPRs was found based on a comprehensive computational study of a correlation between the functional annotations in the Swiss-Prot database and predicted intrinsic disorder.
T104 51656-51953 Epistemic_statement denotes [138] [139] [140] The approach was based on the hypothesis that if a function described by a given keyword relies on intrinsic disorder, then the keyword-associated protein would be expected to have a greater level of predicted disorder compared to the protein randomly chosen from the Swiss-Prot.
T105 51954-52192 Epistemic_statement denotes This analysis revealed that 44% and 34% of Swiss-Prot functional keywords were associated with ordered and disordered proteins, respectively, whereas 22% functional keywords yielded ambiguity in the likely function-structure associations.
T106 52193-52436 Epistemic_statement denotes [138] [139] [140] Interestingly, most of the structured protein-associated key words were shown to be related to enzymatic activities, whereas the majority of the disordered protein-associated keywords were related to signaling and regulation.
T107 52437-52711 Epistemic_statement denotes These results agree well with the notion that enzymatic catalysis requires ordered structure and that effectiveness of signaling is dependent on binding reversibility, a property directly associated with the thermodynamics of disorder-to-order transition induced by binding.
T108 52806-53173 Epistemic_statement denotes 11, 13, 15, 71, 72, 78, 79, [130] [131] [132] 134, [154] [155] [156] [157] When disordered regions bind to signaling partners, the free energy required to bring about the disorder to order transition takes away from the interfacial, contact free energy, with the net result that a highly specific interaction can be combined with a low net free energy of association.
T109 53296-53422 Epistemic_statement denotes Furthermore, a disordered protein can readily bind to multiple partners by changing shape to associate with different targets.
T110 53423-53742 Epistemic_statement denotes 13, 158, 159 All this clearly suggests that there is a new twopathway protein structure-function paradigm, with sequence-to-structure-to-function for enzymes and membrane transport proteins, and sequence-to-disordered ensemble-to-function for proteins and protein regions involved in signaling, regulation, and control.
T111 53743-54038 Epistemic_statement denotes 1, 13, 71, 73, 79 One of the first generalization of this concept was given by The Protein Trinity Hypothesis, which suggested that native proteins can be in one of three states, the solid-like ordered state, the liquid-like collapsed-disordered state, or the gas-like extended-disordered state.
T112 54722-55164 Epistemic_statement denotes 141, 165 Since all these functions illustrate the notions that the intrinsic disorder concept represents a universal skeleton key (or lock-pick) that helps unlocking seemingly unresolvable mysteries of protein science and therefore can be considered as a new Ariadne's thread that helps navigate the unusual twists of the sophisticated relationships between protein sequence, structure, and function, they are considered in some detail below.
T113 56017-56216 Epistemic_statement denotes 137 In addition to these mechanisms that can be explained within the frames of the traditional structure-function paradigm, consideration of the intrinsic disorder phenomenon opens new possibilities.
T114 57046-57302 Epistemic_statement denotes Signaling interactions inside the cell can be described as specific and complex networks that can be considered as "scale-free" or "small-world" networks, which have hubs, with many connections, and ends, that have the only connection to just one neighbor.
T115 57303-57520 Epistemic_statement denotes 170, 171 Such scale-free networks combine the local clustering of connections characteristic of regular networks with occasional long-range connections between clusters, as can be expected to occur in random networks.
T116 57853-58047 Epistemic_statement denotes 173 Since many IDPs are known to be involved in interaction with large number of distinct partners, they clearly can be considered as hubs in the scale-free protein-protein interaction networks.
T117 58809-59526 Epistemic_statement denotes 160 Besides being responsible for bringing together specific proteins within a signaling pathway and providing selective spatial orientation and temporal coordination to facilitate and promote interactions among interacting proteins, some scaffolds can influence the specificity and kinetics of signaling interactions via simultaneous binding to multiple participants in a particular pathway and facilitation and/or modifying the specificity of pathway interactions, 174 other scaffold can change conformations of individual proteins and thus modulate their activities, 174 still other scaffold proteins may modulate the activation of alternative pathways by promoting interactions between various signaling proteins.
T118 59527-59678 Epistemic_statement denotes 141 Analysis of several well-characterized signaling scaffold proteins reveled that their large IDPRs are crucial for the successful scaffold function.
T119 59934-60119 Epistemic_statement denotes 165 This gave further support to the notion that signaling scaffold proteins utilize the various features of highly flexible ID regions to obtain more functionality from less structure.
T120 60163-60283 Epistemic_statement denotes Conformational plasticity and adaptability associated with intrinsic disorder are crucial for various protein functions.
T121 60547-60709 Epistemic_statement denotes 179 For example, from 83 to 94% of TFs might possess long IDPRs, with the degree of disorder in eukaryotic TFs being significantly higher than in prokaryotic TFs.
T122 61083-61423 Epistemic_statement denotes However, the AT-hooks (which are DNA-binding motifs present in many proteins which binds to the (ATAA) and (TATT) repeats of DNA) and basic regions of TF DNA-binding domains are highly disordered suggesting that eukaryotes with their well-developed gene transcription machinery require transcription factor flexibility to be more efficient.
T123 62366-62532 Epistemic_statement denotes This pathway is known to play a number of crucial roles in the development of organism, and the malfunctions of which might lead to various diseases including cancer.
T124 63787-63944 Epistemic_statement denotes These modules are not only tightly regulated but also intimately interconnected and are jointly controlled via a complex set of protein-protein interactions.
T125 64603-64607 Epistemic_statement denotes 183
T126 64608-64701 Epistemic_statement denotes Unique catalytic function of a protein is believed to be dictated by its unique 3D structure.
T127 65682-65900 Epistemic_statement denotes 185 Furthermore, in general, dynamic fluctuations are crucial for enzyme catalysis, since they can influence substrate binding and product release, and may even adjust the effective barriers of the catalyzed reactions.
T128 65901-66241 Epistemic_statement denotes [186] [187] [188] [189] [190] Often, dynamic changes in the enzyme during the catalytic reaction can be described using the induced-fit model, where a conversion of one tight conformational ensemble (free enzyme) to another distinct ensemble (bound enzyme) takes place through a series of local substrate-mediated structural rearrangements.
T129 66542-66839 Epistemic_statement denotes From this viewpoint, the presence of intrinsic disorder is expected to be poorly compatible with enzymatic catalysis, which requires a well-organized environment in the active site of the enzyme in order to facilitate the formation of the transition state of the chemical reaction to be catalyzed.
T130 66840-67222 Epistemic_statement denotes 192 In a sharp contrast to this common wisdom supported by a wide array of specific examples, several enzymes were shown to be much more dynamic than the catalytic machines are expected to be, clearly possessing, in their precatalytic states, many characteristic properties of molten globules and retaining unusually high flexibility in structurally defined enzyme-ligand complexes.
T131 67738-67950 Epistemic_statement denotes 193 Interaction with natural ligand induced global conformational changes in the molten globular mMjCM promoting formation of a defined enzyme-ligand complex, which, however, preserved unusually high flexibility.
T132 67951-68277 Epistemic_statement denotes 184 Catalytic mechanism of the molten globular mMjCM was described as follows: "Though probably stochastic in nature, internal motions in the complex may generate a collective dynamic matrix that samples catalytically active conformation(s) often enough to achieve rapid turnover in the presence of the true transition state."
T133 68278-68426 Epistemic_statement denotes 184 Therefore, some enzymes can represent a highly dynamic heterogeneous conformational ensemble which is still compatible with efficient catalysis.
T134 68427-68615 Epistemic_statement denotes In agreement with this hypothesis, a molten globular character was described for circularly permuted dihydrofolate reductase (DHFR), 196, 197 and urease G from Bacillus pasteurii (BpUreG).
T135 68850-69008 Epistemic_statement denotes Although the number of known native molten globules with enzymatic activity is small, their existence provides an interesting hint on early protein evolution.
T136 69009-69235 Epistemic_statement denotes In fact, simple logics suggests that well-ordered enzymes appear as a result of long evolutionary process, whose very likely starting point was a partially folded polypeptide with some general properties of the molten globule.
T137 69236-69434 Epistemic_statement denotes IDPs/IDPRs can form highly stable complexes, or be involved in signaling interactions where they undergo constant "bound-unbound" transitions, thus acting as dynamic and sensitive "on-off" switches.
T138 71300-71489 Epistemic_statement denotes Such mode of interaction was recently described as "the flanking fuzziness" in contrast to "the random fuzziness" when the disordered protein remains entirely disordered in the bound state.
T139 71490-71659 Epistemic_statement denotes 75, 212 It is also expected that the similar binding mode can be utilized by disordered protein while interacting with nucleic acids and other biological macromolecules.
T140 71660-71787 Epistemic_statement denotes 201 Physically, binding is considered as joining objects together and suggests spatial and temporal fixation of bound partners.
T141 71788-71920 Epistemic_statement denotes The formation of protein complexes with specific binding partners is expected to bring some fixation (at least at the binding site).
T142 71921-72169 Epistemic_statement denotes Therefore, disordered complexes where interaction of a disordered protein with the binding partners is not accompanied by a disorder-to-order transition within the interaction interface clearly cannot be described by the classical binding paradigm.
T143 72170-72317 Epistemic_statement denotes This contradiction can be resolved assuming that the ordered binding partner and/or disordered protein contain multiple low affinity binding sites.
T144 72318-72615 Epistemic_statement denotes The existence of several similar binding sites combined with a highly flexible and dynamic structure of disordered protein creates a unique situation where any binding site of disordered protein can interact with any binding site of its partner with almost equal probability, in a staccato manner.
T145 72616-72726 Epistemic_statement denotes The low affinity of each individual contact implies that each of them is not stable and can be readily broken.
T146 72727-73024 Epistemic_statement denotes Therefore, such disordered or fuzzy complex can be envisioned as a highly dynamic ensemble in which a disordered protein does not present a single binding site to its partner but resemble a "binding cloud," in which multiple identical binding sites are dynamically distributed in a diffuse manner.
T147 73188-73326 Epistemic_statement denotes 201 An additional factor which can help holding a dynamic complex together could be a weak longrange attraction between protein molecules.
T148 73676-73789 Epistemic_statement denotes However, functions of some ordered proteins require local or even global unfolding of a unique protein structure.
T149 73980-74351 Epistemic_statement denotes 68 These functional unfolding-activating factors include light; mechanical force; changes in pH, temperature, or redox potential; interaction with membrane, ligands, nucleic acids, and proteins; various PTMs; release of autoinhibition due to the unfolding of autoinhibitory domains induced by their interaction with nucleic acids, proteins, membranes, PTMs, and so forth.
T150 74867-75035 Epistemic_statement denotes The absorption of a photon triggers substantial protein unfolding and leads to the formation of the transient signaling state that interacts with the partner molecules.
T151 75713-75827 Epistemic_statement denotes 68 Some proteins undergo local unfolding induced by the mechanical force and therefore can serve as force sensors.
T152 76860-77096 Epistemic_statement denotes However, one need to keep in mind that a portion of "folding code" that defines the ability of ordered proteins to spontaneously gain a unique biologically active structure is missing for IDPs/IDPRs since they cannot fold spontaneously.
T153 77097-77200 Epistemic_statement denotes This missing portion of the "folding code" (or a part of it) can be supplemented by binding partner(s).
T154 77201-77533 Epistemic_statement denotes As a result, ordered and disordered proteins can be discriminated on a simple basis of temporal correlation between their folding and binding: ordered proteins fold first and then bind to their partners while the IDPs/IDPRs remain disordered until they bind their partners and often preserve substantial disorder in the bound state.
T155 77534-77839 Epistemic_statement denotes 69 Furthermore, numerous cases of functional unfolding (or transient disorder, or upside-down functionality) represent further support to the concept of functional disorder by clearly showing that many proteins possess dormant disorder that needs to be awakened in order to make these proteins functional.
T156 77840-77923 Epistemic_statement denotes It is clear now that the IDPs and IDPRs are real, abundant, diversified, and vital.
T157 78007-78218 Epistemic_statement denotes However, the evolutionary persistence of these highly dynamic proteins (see below), their unique functionality, and involvement in all the major cellular processes evidence that this chaos is tightly controlled.
T158 78219-78253 Epistemic_statement denotes 147 To answer the question as to .
T159 79336-79471 Epistemic_statement denotes Then, the correlations between intrinsic disorder and the various regulation steps of protein synthesis and degradation were evaluated.
T160 79587-79771 Epistemic_statement denotes However the IDP-encoding transcripts were generally less abundant than transcripts encoding ordered proteins due to the increased decay rates of the transcripts of genes encoding IDPs.
T161 80401-80605 Epistemic_statement denotes 222 Therefore, PTMs may not only serve as important mechanism for the fine-tuning of the IDP functions but possibly they are necessary to tune the IDP availability under the different cellular conditions.
T162 80729-80934 Epistemic_statement denotes 222 Based on these observations it has been concluded that both unicellular and multicellular organisms appear to use similar mechanisms for regulation of the intrinsically disordered protein availability.
T163 81088-81268 Epistemic_statement denotes This tight control is directly related to the major roles of IDPs in signaling, where it is crucial to be available in appropriate amounts and not to be present longer than needed.
T164 81269-81629 Epistemic_statement denotes 222 It has been also pointed out that although the abundance of many IDPs is under strict control, some IDPs could be present in cells in large amounts or/and for long periods of time due to either specific PTMs or via interactions with other factors, which could promote changes in cellular localization of IDPs or protect them from the degradation machinery.
T165 81630-81798 Epistemic_statement denotes 13, 70, 138, 223, 224 Overall, this study clearly showed that the chaos seemingly introduced into the protein world by the discovery of IDPs is under the tight control.
T166 81799-81954 Epistemic_statement denotes 147 In an independent study, a global scale relationship between the predicted fraction of protein disorder and protein expression in E. coli was analyzed.
T167 81955-82187 Epistemic_statement denotes 225 This study showed that the fraction of protein disorder was positively correlated with both measured RNA expression levels of E. coli genes in three different growth media and with predicted abundance levels of E. coli proteins.
T168 82188-82409 Epistemic_statement denotes 225 When a subset of 216 E. coli proteins that are known to be essential for the survival and growth of this bacterium were analyzed, the correlation between protein disorder and expression level became even more evident.
T169 82935-83167 Epistemic_statement denotes 225 A direct link between protein disorder and protein level in E. coli cells could be because the IDPs may carry out the essential control and regulation functions that are needed to respond to the various environmental conditions.
T170 83168-83348 Epistemic_statement denotes Another possibility is that IDPs might undergo more rapid degradation compared to structured proteins, which cells can counter by increasing mRNA levels of the corresponding genes.
T171 83349-83581 Epistemic_statement denotes In this case, higher synthesis and degradation rates could make the levels of these proteins very sensitive to the environment, with slight changes in either production or degradation leading to significant shifts in protein levels.
T172 83582-83731 Epistemic_statement denotes 225 Even more support for the tight control of IDPs inside the cell came from the analysis of cellular regulation of so-called "vulnerable" proteins.
T173 83732-83902 Epistemic_statement denotes 23 The integrity of the soluble protein functional structures is maintained in part by a precise network of hydrogen bonds linking the backbone amide and carbonyl groups.
T174 84099-84434 Epistemic_statement denotes 226, 227 Since soluble protein structures may be more or less vulnerable to water attack depending on their packing quality, a structural attribute, protein vulnerability, was introduced as the ratio of solvent-exposed backbone hydrogen bonds (which represent local weaknesses of the structure) to the overall number of hydrogen bonds.
T175 84435-84725 Epistemic_statement denotes 23 It has been also pointed out that structural vulnerability can be related to protein intrinsic disorder as the inability of a particular protein fold to protect intramolecular Uversky hydrogen bonds from water attack may result in backbone hydration leading to local or global unfolding.
T176 84726-84954 Epistemic_statement denotes Since binding of a partner can help to exclude water molecules from the microenvironment of the preformed bonds, a vulnerable soluble structure gains extra protection of its backbone hydrogen bonds through the complex formation.
T177 84955-85191 Epistemic_statement denotes 226 To understand the role of structure vulnerability in transcriptome organization, the relationship between the structural vulnerability of a protein and the extent of co-expression of genes encoding its binding partners was analyzed.
T178 85192-85342 Epistemic_statement denotes This study revealed that structural vulnerability can be considered as a determinant of transcriptome organization across tissues and temporal phases.
T179 85343-85739 Epistemic_statement denotes 23 Finally, by interrelating vulnerability, disorder propensity and co-expression patterns, the role of protein intrinsic disorder in transcriptome organization was confirmed, since the correlation between the extent of intrinsic disorder of the most disordered domain in an interacting pair and the expression correlation of the two genes encoding the respective interacting domains was evident.
T180 86442-87089 Epistemic_statement denotes 234, 235 An illustrative examples of human neurodegenerative diseases associated with IDPs includes Alzheimer's disease (deposition of amyloid-b, tau-protein, a-synuclein fragment NAC) [236] [237] [238] [239] ; various taupathies (accumulation of tau-protein in the form of neurofibrillary tangles) 238 ; Down's syndrome (nonfilamentous amyloid-b deposits) 240 ; Parkinson's disease and other synucleinopathies (deposition of asynuclein) 241 ; prion diseases (deposition of PrP SC ) 242 ; and a family of polyQ diseases, a group of neurodegenerative disorders caused by expansion of GAC trinucleotide repeats coding for PolyQ in the gene products.
T181 87090-87361 Epistemic_statement denotes 243 Furthermore, most mutations in rigid globular proteins associated with accelerated fibrillation and protein deposition diseases have been shown to destabilize the native structure, increasing the steady-state concentration of partially folded (disordered) conformers.
T182 87582-87649 Epistemic_statement denotes However, there is another side to this coin: protein functionality.
T183 88347-88542 Epistemic_statement denotes The choice between these conformations is determined by the peculiarities of the protein environment, suggesting that asynuclein has an exceptional ability to fold in a template-dependent manner.
T184 88543-88733 Epistemic_statement denotes Therefore, the development of the conformational diseases may originate not only from misfolding but also from the misidentification, misregulation, and missignaling of the related proteins.
T185 88734-88812 Epistemic_statement denotes Analysis of so-called polyglutamine diseases gives support to this hypothesis.
T186 89388-89585 Epistemic_statement denotes 248 It has been emphasized that such molecular processes as unfolded protein response, protein transport, synaptic transmission, and transcription are implicated in the pathology of polyQ diseases.
T187 89863-90047 Epistemic_statement denotes These results suggest that polyQ diseases represent kind of transcriptional disorder, 244 supporting our misidentification hypothesis for at least some of the conformational disorders.
T188 91925-91934 Epistemic_statement denotes 259, 260
T189 91935-92147 Epistemic_statement denotes The possibility of interrupting the action of diseaseassociated proteins (including through modulation of protein-protein interactions) presents an extremely attractive objective for the development of new drugs.
T190 92148-92462 Epistemic_statement denotes Since many proteins associated with various human diseases are either completely disordered or contain long disordered regions, 261, 262 and since some of these disease-related IDPs/IDPRs are involved in recognition, regulation, and signaling, these proteins/regions clearly represent novel potential drug targets.
T191 92790-92965 Epistemic_statement denotes While generally applicable to many enzymatic domains, this view has persisted to influence thinking concerning all protein functions despite numerous examples to the contrary.
T192 92966-93221 Epistemic_statement denotes This is most apparent in the observation that the vast majority of currently available drugs target the active site of enzymes, presumably since these are the only proteins for which the "unique structure-unique function" paradigm is generally applicable.
T193 93317-93447 Epistemic_statement denotes [263] [264] [265] Targeting disorder-based interactions should enable the development of more effective drug discovery techniques.
T194 93694-93854 Epistemic_statement denotes The principles of small molecule binding to IDPRs have not been well studied, but sequence specific, small molecule binding to short peptides has been observed.
T195 93855-94077 Epistemic_statement denotes 266 An interesting twist here is that small molecules can inhibit disorder-based proteinprotein interactions via induction of the dysfunctional ordered structures in targeted IDPR, that is, via the drug-induced misfolding.
T196 95456-95633 Epistemic_statement denotes 260, [268] [269] [270] This successful nutlin story marks the potential beginning of a new era, the signaling-modulation era, in targeting drugs to protein-protein interactions.
T197 96154-96306 Epistemic_statement denotes 271 Therefore, the p53-Mdm2 complex is not a unique exception and many other disorderbased protein-protein interactions are blocked by a small molecule.
T198 96307-96446 Epistemic_statement denotes All this suggest that there is a cornucopia of new drug targets that would operate by blocking disorder-based protein-protein interactions.
T199 96825-97053 Epistemic_statement denotes 25 Methods for predicting such binding sites in disordered regions have been developed 274 and the bioinformatics tools to identify which disordered binding regions can be easily mimicked by small molecules have been elaborated.
T200 97264-97499 Epistemic_statement denotes 275 In order to bind DNA, regulate expression of target genes, and function in most biological contexts, c-Myc transcription factor must dimerize with its obligate heterodimerization partner, Max, which lacks a transactivation segment.
T201 97706-97868 Epistemic_statement denotes Since the deregulation of c-Myc is related to many types of cancer, the disruption of the c-Myc-Max dimeric complex is one of the approaches for c-Myc inhibition.
T202 97946-98191 Epistemic_statement denotes 275 These molecules were shown to bind to one of the three discrete sites within the 85-residue bHLHZip domain of c-Myc, which are composed of short contiguous stretches of amino acids that can selectively and independently bind small molecules.
T203 98465-98702 Epistemic_statement denotes Based on these observations it has been concluded that a rational and generic approach to the inhibition of protein-protein interactions involving IDPs may therefore be possible through the targeting of intrinsically disordered sequence.
T204 99061-99268 Epistemic_statement denotes However, detailed analyses of the conformational behavior and fine structure of several IDPs revealed that the preformed binding elements might be involved in a set of non-native intramolecular interactions.
T205 99269-99606 Epistemic_statement denotes Based on these observations it was proposed that an intrinsically disordered polypeptide chain in its unbound state can be misfolded to sequester the preformed elements inside the noninteractive or less-interactive cage, therefore preventing these elements from the unnecessary and unwanted interactions with non-native binding partners.
T206 99607-99773 Epistemic_statement denotes 276 It is important to remember, however, that the mentioned functional misfolding is related to the ensemble behavior of transiently populated elements of structure.
T207 99774-100029 Epistemic_statement denotes In other words, it describes the behavior of a globally disordered polypeptide chain containing highly dynamic elements of residual structure, so-called interaction-prone preformed fragments, some of which could potentially be related to protein function.
T208 100030-100303 Epistemic_statement denotes 276 This ability of IDRPs/IDPRs to functionally misfold can be used for finding small molecules which would potentially stabilize different members of the functionally misfolded ensemble, and therefore prevent the targeted protein from establishing biological interactions.
T209 100551-100704 Epistemic_statement denotes In essence, this approach can be considered as an extension of the well-established structure-based rational drug design elaborated for ordered proteins.
T210 100705-101019 Epistemic_statement denotes In fact, if the structure of a member(s) of the functionally misfolded ensemble can be guessed, then this structure can be used to find small molecules that are potentially able to interact with this structure, utilizing tools originally developed for the rational structure-based drug design for ordered proteins.
T211 101020-101115 Epistemic_statement denotes 277 Ideally, a drug that targets a given protein-protein interaction should be tissue specific.
T212 101116-101262 Epistemic_statement denotes Although some proteins are unique for a given tissue, many more proteins have very wide distribution, being present in several tissues and organs.
T213 101263-101338 Epistemic_statement denotes How can one develop tissue-specific drugs targeting such abundant proteins?
T214 101537-101657 Epistemic_statement denotes Estimates indicate that between 35 and 60% of human genes yield protein isoforms by means of alternatively spliced mRNA.
T215 101658-101828 Epistemic_statement denotes 278 The added protein diversity from alternative splicing is thought to be important for tissue-specific signaling and regulatory networks in the multicellular organisms.
T216 101829-102061 Epistemic_statement denotes The regions of alternative splicing in proteins are enriched in intrinsic disorder, and it was proposed that associating alternative splicing with protein disorder enables the time-and tissue-specific modulation of protein function.
T217 102062-102251 Epistemic_statement denotes 152 Since disorder is frequently utilized in protein binding regions, having alternative splicing of pre-mRNA coupled to IDPRs can define tissue-specific signaling and regulatory diversity.
T218 102252-102572 Epistemic_statement denotes 152 These findings open a unique opportunity to develop tissue-specific drugs modulating the function of a given ID protein/region (with a unique profile of disorder distribution) in a target tissue and not affecting the functionality of this same protein (with different disorder distribution profile) in other tissues.
T219 102573-102700 Epistemic_statement denotes Wavy pattern of global evolution of intrinsic disorder IDPs/IDPRs are more common in eukaryotes than in less complex organisms.
T220 102701-102975 Epistemic_statement denotes 43, 44, [48] [49] [50] [51] [52] This suggests that disorder, with its ability to be implemented in various signaling, recognition, and regulation pathways and networks, is important for the maintenance of life in eukaryotic and especially muticellular eukaryotic organisms.
T221 102976-103358 Epistemic_statement denotes 4, 45, 78, 134 Also, the finding that alternatively spliced regions of mRNA code for IDPRs much more often than for structured regions suggests that there is a linkage between alternative splicing and signaling by IDPRs that constitutes a plausible mechanism that could underlie and support cell differentiation, which ultimately gave rise to the multicellular eukaryotic organisms.
T222 103359-103467 Epistemic_statement denotes 152 Therefore, one can assume that intrinsic disorder represents a relatively recent evolutionary invention.
T223 103468-103577 Epistemic_statement denotes However, this hypothesis obviously would be wrong if earlier stages of evolution would be taken into account.
T224 103858-104040 Epistemic_statement denotes There are still debates and different theories about what happened in those years between the time the earth was cool enough to spawn life and the time the first fossils were formed.
T225 104041-104400 Epistemic_statement denotes At the beginning of the 20th century, Oparin 279 and Haldane 280 proposed that some organic molecules could have been spontaneously produced from the gases of the primitive Earth atmosphere, assuming that this primitive atmosphere was reducing (as opposed to oxygen-rich), and there was an appropriate supply of energy, such as lightning or ultraviolet light.
T226 104401-105008 Epistemic_statement denotes Thirty year later, this hypothesis (that constitutes a cornerstone of the theory of molecular evolution) received strong support from the elegant experiments of Stanley L. Miller and Harold C. Urey who were able to synthesize various organic compounds including some amino acids from non-organic compounds which were believed to represent the major components of the early Earth's atmosphere (water vapor, hydrogen, methane, and ammonia) by putting them into a closed system and running a continuous electric current through the system, to simulate lightning storms believed to be common on the early Earth.
T227 105009-105199 Epistemic_statement denotes 281, 282 However, the Miller-Urey experiment yielded only about half of the modern amino acids 281, 282 suggesting that the first proteins on Earth may have contained only a few amino acids.
T228 105200-105496 Epistemic_statement denotes These findings go in parallel with the biosynthetic theory of the genetic code evolution suggesting that the genetic code evolved from a simpler form that encoded fewer amino acids, 283 probably paralleled by the invention of biosynthetic pathways for new and chemically more complex amino acids.
T229 105497-105740 Epistemic_statement denotes 284 Furthermore, some additional support of the validity of this hypothesis can be found in the standard genetic code (that consists of 4 3 4 3 4 5 64 triplets of nucleotides, codons), which is redundant (64 codons encodes for 20 amino acids).
T230 105741-105850 Epistemic_statement denotes In fact, with only two exceptions, codons encoding one amino acid may differ in any of their three positions.
T231 105851-106060 Epistemic_statement denotes However, only the third positions of some codons may be fourfold degenerate, that is, any nucleotide at this position specifies the same amino acid and all nucleotide substitutions at this site are synonymous.
T232 106061-106406 Epistemic_statement denotes Using these observations as a reflection of the evolutionary development, it was proposed that there was a period during code evolution where the third position was not needed at all and a doublet code preceded the triplet code, giving rise to 4 3 4 5 16 codons encoding for 16 or fewer amino acids, if a termination codon is taken into account.
T233 106407-106509 Epistemic_statement denotes 285 Based on these and many other premises, one can discriminate evolutionary old and new amino acids.
T234 107955-108041 Epistemic_statement denotes This strongly suggests that the primordial polypeptides were intrinsically disordered.
T235 108042-108137 Epistemic_statement denotes It is very unlikely that these disordered primordial polypeptides possessed catalytic activity.
T236 108138-108348 Epistemic_statement denotes 287 This hypothesis is in line with the RNA world theory suggesting that during the evolution of enzymatic activity, catalysis was transferred from RNA first to ribonucleoprotein (RNP) and only then to protein.
T237 108349-108527 Epistemic_statement denotes 288 Therefore, the first proteins in the "breakthrough organism" (the first to have encoded protein synthesis) would be nonspecific chaperone-like proteins rather than catalysts.
T238 109474-109787 Epistemic_statement denotes Here, primordial proteins are expected to be mostly disordered (left-hand side of the plot), proteins in LUA likely are mostly structured (center of the plot), whereas many protein in eukaryotes are either totally disordered or hybrids containing both ordered and disordered regions (right-hand side of the plot).
T239 109788-109992 Epistemic_statement denotes nucleotides and since protein structures are noticeably more stable than RNA structures, the transition from RNAs (ribozymes) to proteins as carriers of enzymatic activity was a logical evolutionary step.
T240 109993-110119 Epistemic_statement denotes However, efficient catalysis relies on the proper spatial arrangement of catalytic residues which requires a stable structure.
T241 110361-110662 Epistemic_statement denotes 5 (B)], where highly disordered primordial proteins with primarily RNA-chaperone activities were gradually substituted by the well-folded, highly ordered enzymes that evolved to catalyze the production of all the complex "goodies" crucial for the independent existence of the first cellular organisms.
T242 110663-111085 Epistemic_statement denotes Due to its specific features crucial for the regulation of complex processes, protein intrinsic disorder was reinvented at the subsequent evolutionary steps leading to the development of more complex organisms from the last universal ancestor (i.e., the most recent organism from which all organisms now living on Earth descend 293, 294 ) , and culminating in the appearance of the highly elaborated eukaryotic cells [see
T243 111086-111218 Epistemic_statement denotes There is no simple answer to the question on the comparative evolutionary rates of ordered and IDPs and regions in modern organisms.
T244 111219-111363 Epistemic_statement denotes In fact, it looks like everything is possible, and intrinsically disordered sequences may evolve faster, slower or similar to ordered sequences.
T245 112016-112446 Epistemic_statement denotes 151, 301 Furthermore, based on the observation that a significantly higher degree of positive Darwinian selection was observed in IDPRs of proteins compared to regions of a-helix, b-sheet or tertiary structures, it was hypothesized that IDPRs may be required for the genetic variation with adaptive potential and that these regions may be of "central significance for the evolvability of the organism or cell in which they occur."
T246 113510-113658 Epistemic_statement denotes 151 Also, even different parts of the same disordered region can possess noticeable variability in their divergence during the evolutionary process.
T247 113659-113797 Epistemic_statement denotes 308 Finally, in some disordered proteins, peculiarities of the amino acid composition, and not the amino acid sequence might be conserved.
T248 114189-114403 Epistemic_statement denotes The work which started in my group as an attempt to understand what is so special about several natively unfolded proteins produced a real explosion of interest to structure-less proteins with biological functions.
T249 114528-114710 Epistemic_statement denotes There is no need to list once again all the discoveries and findings made in this field-they are subjects of many recent reviews and some of them are briefly covered in this article.
T250 114711-115082 Epistemic_statement denotes Although the amount of data generated during the past decade and a half on specific features related to the structural properties of IDPs and IDPRs, their abundance, distribution, functional repertoire, regulation, involvement into the disease pathogenesis, and so forth is vast, it seems that this mass of data produced so far is just a small tip of a humongous iceberg.
T251 115083-115199 Epistemic_statement denotes IDPs/IDPRs continue to bring discoveries almost on a daily basis and even more breakthroughs are expected in future.