LitCovid-sentences  

PMC:7556165 / 35226-44912 JSONTXT 16 Projects

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Id Subject Object Predicate Lexical cue
T216 0-50 Sentence denotes Mechanism of Viral Entry Mediated by the S Protein
T217 51-176 Sentence denotes A coronavirus contains four structural proteins, namely spike (S), envelope (E), membrane (M), and nucleocapsid (N) proteins.
T218 177-303 Sentence denotes These proteins assemble around a lipid bilayer to provide the shell enclosing the viral genome (Figure 4A; Tang et al., 2020).
T219 304-495 Sentence denotes Homotrimers of S protrude from the viral surface, and are densely decorated by N-linked glycans, creating the “crown” (“Corona” in Latin) that christens this virus group (Walls et al., 2016).
T220 496-650 Sentence denotes S is a ∼180 kDa glycoprotein anchored in the viral membrane, which plays the most important roles in viral attachment, fusion and entry (Ou et al., 2020).
T221 651-801 Sentence denotes Sequence analysis has shown that SARS-CoV-2 S protein shares 76% of the primary sequence with the corresponding S of human SARS-CoV (Ou et al., 2020).
T222 802-932 Sentence denotes Accordingly, it has been early proposed that SARS-CoV-2 utilizes a similar cell entry mechanism as SARS-CoV, pivoted on S protein.
T223 933-1003 Sentence denotes This hypothesis has been confirmed from an experimental point of view.
T224 1004-1216 Sentence denotes By using pseudotyped virus bearing SARS-CoV S or SARS-CoV-2 S, it was shown that a large panel of cell lines allows comparable entry of SARS-CoV or SARS-CoV-2 viruses (Hoffmann et al., 2020b; Walls et al., 2020).
T225 1217-1349 Sentence denotes FIGURE 4 (A) Structure of a Coronavirus. (B) Functional motifs in the sequence of the S “spike” protein of SARS-CoV and SARS-CoV-2.
T226 1350-1631 Sentence denotes The S protein consists of ∼1300 aminoacids and it is composed by a N-terminal “S1”subunit (∼700 aa) and a C-terminal “S2”subunit (∼600 aa); binding to the host receptor is mediated by S1, whereas S2 induces fusion of the viral envelope with cellular membranes (Walls et al., 2017).
T227 1632-1758 Sentence denotes S1 and S2 can be further subdivided in functional segments with different roles in viral entry (Figure 4B; Tang et al., 2020).
T228 1759-1859 Sentence denotes The S1 subunit contains two subdomains, the N-terminal domain (NTD) and the C-terminal domain (CTD).
T229 1860-2063 Sentence denotes In SARS-CoV (Li, 2015) and SARS-CoV-2 (Wang et al., 2020) CTD encloses the receptor-binding domain (RBD), and the RBD section that directly contacts the receptor is named as receptor-binding motif (RBM).
T230 2064-2217 Sentence denotes The N-region of S2 contains a fusion peptide (FP), two heptapeptide repeat domains (HR1, HR2), a transmembrane domain (TM), and cytoplasmic peptide (CP).
T231 2218-2385 Sentence denotes FP is a short segment composed of mostly hydrophobic residues, such as glycine (G) or alanine (A), which inserts in the host cell membrane to trigger the fusion event.
T232 2386-2569 Sentence denotes HR1 and HR2 are composed of a repetitive heptapeptide with HPPHCPC sequence, where H represents hydrophobic or bulky residues, P polar or hydrophilic residues, and C charged residues.
T233 2570-2668 Sentence denotes HR regions typically fold into α-helices with a hydrophobic interface that drives membrane fusion.
T234 2669-2866 Sentence denotes On the basis of the strong similarity between the S proteins of SARS-CoV and SARS-CoV-2, many researchers early set-out to demonstrate whether both viruses target the same host cell receptor, ACE2.
T235 2867-3025 Sentence denotes Zhou et al. (2020) highlighted that the virus was able to infect cell lines only when they expressed human, bat, civet, and pig (but not mouse) ACE2 receptor.
T236 3026-3217 Sentence denotes Hoffmann et al. (2020b), Ou et al. (2020), and Walls et al. (2020) elegantly outlined that the BHK cell line could be infected by pseudotyped SARS-CoV-2 or SARS-CoV only upon ACE2 expression.
T237 3218-3423 Sentence denotes Conversely, the expression of different human receptors used by other CoVs (hDPP4 and APN, used by MERS CoV and HCoV-229E, respectively) did not enable pseudovirus access to cells (Hoffmann et al., 2020b).
T238 3424-3518 Sentence denotes Taken together, these findings are solid evidence that SARS-CoV-2 engages ACE2 for cell entry.
T239 3519-3742 Sentence denotes Nonetheless, the two viruses were demonstrated by Xia to share also the membrane fusion mechanism, as strongly suggested by the impressive 89.9% sequence identity of S2 between SARS-CoV and SARS-CoV-2 (Xia et al., 2020a,b).
T240 3743-3968 Sentence denotes To date, the cell entry mechanism of SARS-CoV and SARS-CoV-2 has been understood in its general details and it is based on a concerted action of receptor binding and proteolysis of the S protein (Figure 5; Tang et al., 2020).
T241 3969-4160 Sentence denotes Ultrastructural studies showed a metastable “prefusion” V-shaped trimer composed by three S1 heads sitting on top of a trimeric S2 stalk anchored into the virus membrane (Walls et al., 2016).
T242 4161-4378 Sentence denotes The RBD constantly switches between a standing-up (“open”) position for receptor binding and a lying-down (“closed”) configuration, the latter allowing immune evasion (Figure 6; Song et al., 2018; Wrapp et al., 2020).
T243 4379-4497 Sentence denotes Yet only one of the three RBD in trimeric S can flip up at a time and interact with the receptor (Wrapp et al., 2020).
T244 4498-4660 Sentence denotes The second key feature of the fusion mechanism is “priming” by host proteases, which recognize and cleave a short peptide motif at the S1/S2 boundary (Figure 4B).
T245 4661-5024 Sentence denotes This cleavage does not disassemble S1 from S2 in pre-fusion conditions (Belouzard et al., 2009), but the binding interaction of RBD with its receptor, accompanied by a further cleavage in a second site in S2 (S2’site, upstream of FP, Figure 4B), triggers the possible dissociation of S1 and the irreversible refolding of S2 into a “post-fusion” state (Figure 4B).
T246 5025-5260 Sentence denotes In detail, HR1 undergoes a dramatic “jack-knife” conformational change, converting four helical stretches that run in an antiparallel fashion into a single long (∼130 aa) α-helix (Heald-Sargent and Gallagher, 2012; Walls et al., 2017).
T247 5261-5375 Sentence denotes At first, three of these helices assemble into a homotrimeric bundle and stick the FP into the host cell membrane.
T248 5376-5530 Sentence denotes Then, HR2 (one for each S2 chain) fold backward and bind to HR1, yielding the “six-helix bundle fusion core” (6-HB) of post-fusion S2 (Song et al., 2018).
T249 5531-5763 Sentence denotes This conformational foldback brings the FP (at N-terminus of HR1) and the TM (at the C terminus of HR2) close to each other, so that the viral and host cell membranes approach until their outer leaflets merge (hemifusion, Figure 5).
T250 5764-5974 Sentence denotes Eventually the inner leaflets merge (pore formation), enabling a connection between the interior of the virus and the host cell cytoplasm, that allows the delivery of viral genome (Figure 5; Tang et al., 2020).
T251 5975-6024 Sentence denotes FIGURE 5 Coronavirus viral fusion pathway model.
T252 6025-6088 Sentence denotes Initially, the S protein is in the pre-fusion native state (1).
T253 6089-6387 Sentence denotes Then S undergoes priming of the S1 subunit at S1/S2 by local proteases yielding the pre-fusion metastable state (2); note that priming at S1/S2 could also happen upon virus formation in releasing cell: in such a case the virus attaches to a host cell already in the pre-fusion metastable state (2).
T254 6388-6567 Sentence denotes Subsequent triggering by a protease on S2’ enables the FP to insert in the host membrane upon the “jack-knife” transition of HR1 and HR2 yielding the pre-hairpin intermediate (3).
T255 6568-6682 Sentence denotes The pre-hairpin folds back on itself due to HR1 and HR2 interactions eventually forming the post-fusion (6) state.
T256 6683-6853 Sentence denotes During the S protein foldback, the two membranes approach each other until the outer leaflets merge (hemifusion) and eventually the inner leaflets merge (pore formation).
T257 6854-6975 Sentence denotes Note that cell membrane may refer to plasma membrane (direct fusion) or endosomal membrane (fusion in endocytic vesicle).
T258 6976-7008 Sentence denotes Adapted from Tang et al. (2020).
T259 7009-7085 Sentence denotes FIGURE 6 Trimeric S protein of SARS-CoV-2 in the ”Closed” and “Open” forms.
T260 7086-7174 Sentence denotes Note the single RBD protruding out of the V-shaped conformation of the protein assembly.
T261 7175-7223 Sentence denotes The structures have been drawn from PDB 6X2C (R.
T262 7224-7287 Sentence denotes Henderson, 10.1101/2020.05.18.10208) by Mol on the PDB website.
T263 7288-7457 Sentence denotes Although not directly related to ACE2, the role of S “priming” by host cell proteases deserves particular attention in the context of SARS-CoV-2 virus entry and tropism.
T264 7458-7670 Sentence denotes Possibly, the most notable feature of SARS-CoV-2 genome, as compared to SARS-CoV and some related bat coronaviruses, is a four basic aminoacid insert (PRRA) at the S1/S2 junction (Figure 4B; Jaimes et al., 2020).
T265 7671-7826 Sentence denotes This site is potentially cleavable by the protease furin, a proprotein convertase widely recognized to activate the fusion machinery of viral glycoprotein.
T266 7827-8059 Sentence denotes Indeed, many authors showed that pseudoviruses bearing SARS-CoV-2 S were already “primed” (i.e., cleaved) at the S1/S2 boundary by furin upon assembly in the cell, at odds with pseudoviruses bearing SARS-CoV S (Shang et al., 2020a).
T267 8060-8453 Sentence denotes SARS-COV-2 shows a large flexibility with regard to protease priming, which may independently occur by a) furin and furin-like proteases intracellularly, b) trypsin-like proteases such as TMPRSS2 that are present on the host cell membrane (particularly on airway epithelial cells), and 3) endosomal cathepsins activated by a drop in pH (e.g., cathepsin L) (Figure 7; Hoffmann et al., 2020a,b).
T268 8454-8605 Sentence denotes This flexibility could be the crucial factor that explain SARS-CoV-2 cell tropism and the peculiar features of COVID-19 symptoms (Jaimes et al., 2020).
T269 8606-8791 Sentence denotes Additionally, the kind of protease “priming” may determine whether the membrane fusion process occur directly at the plasma membrane or at endosomal level (Tang et al., 2020; Figure 7).
T270 8792-8877 Sentence denotes FIGURE 7 Relevance of S S1/S2 “priming” by host proteases for viral fusion to cells.
T271 8878-9038 Sentence denotes The left cells produce viruses that can be “primed” by endogenous proteases such as furin (blue scissors); other viruses are not primed when they exit the cell.
T272 9039-9264 Sentence denotes The primed viruses (marked by a yellow internal shadow) reach another cell (pathway A), where a membrane protease (e.g., TMPRSS2) may cleave the S2’ site (see Figure RB1b) leading to membrane fusion and delivery of viral RNA.
T273 9265-9575 Sentence denotes Non-primed viruses can deliver their genome by two routes: in B, the virus reaches the cell, is primed on the membrane at both S1/S2 and S2’ by a local protease and then fuse with the plasma membrane; alternatively, in C the virus is internalized by endocytosis and priming/fusion occurs in endocytic vesicles.
T274 9576-9686 Sentence denotes Note that also “primed” viruses may undergo pathway C, depending on their interaction with the recipient cell.