PMC:2724026 / 24062-27585 JSONTXT

{"target":"https://pubannotation.org/docs/sourcedb/PMC/sourceid/2724026","sourcedb":"PMC","sourceid":"2724026","source_url":"https://www.ncbi.nlm.nih.gov/pmc/2724026","text":"Comparison with the all-beta Greek key Ig-like domains\nThe folding of FADD DD can be compared with that of the all-beta Greek key Ig-like domains studied earlier, including TNfn3,11,45 FNfn10,13 CAfn2,14 and TI I279,10 in our laboratory, and CD2d1.15 In the Ig-like domains, tertiary structure is the dominant factor influencing the folding mechanism. These domains exhibit a near-classical nucleation-condensation mechanism where long-range key residues, in the central BCEF strands, interact in the TS to set up the complicated topology; the transition state is an expanded version of the native state, with the folding nucleus involving secondary and tertiary interactions, centred around the structural core. Peripheral regions pack late.\nUnlike the Ig-like domains, FADD DD has three discrete hydrophobic cores. The central core is composed of residues from the central helices H1, H2, H4 and H5; the hydrophobic residues interacting in these helices can be regarded as the structural core of this four-helix bundle. The parallel helices H1-H5 and H2-H4 have to be organised relative to each other to form the Greek key topology; this is analogous to the organisation of the anti-parallel beta strands B-E and C-F relative to each other, in the core of the Ig-like domains. In the Ig-like domains, we infer from the Φ-value analysis that the alignment of strands within the sheet and the packing of the two sheets together occurs concomitantly; these are the critical nucleating events for Ig-like domain folding. Although it is not possible to determine the order of events in the folding of the DD from the Φ-value analysis alone, we can show that helices H2 and H4 come together via the core of B2, whereas helices H1 and H5 require the formation of the central core to come together. In both Greek key structures, many long-range, tertiary interactions are involved in formation and stabilisation of the central core; however, local interactions important for helix formation are also involved in the DD. Interestingly, simulations of the TS for folding in the Ig-like protein TNfn3 suggested that the four strands form an “open horseshoe” structure, with all four central strands connected, but with the “ring” of structures incomplete.45 This is reminiscent of what we observe in FADD DD with all four central helices in contact, but where the packing of H4 into the central core is only marginal. Another similarity with the Ig-like domains is the observation that the elements of secondary structure most peripheral to the central core are relatively unimportant in formation of the TS structure. In the Ig-like domains, the two beta strands at the N- and C-termini are not involved in forming the structural core, and these fold late. In the DD fold, the N-terminal helix H1 is involved in forming the central core, but H3 and the C-terminal helix H6 are both peripheral to the structure and not involved in packing the central hydrophobic core. The Φ-value analysis suggests that these peripheral helices are either completely unfolded (H3) or attached only loosely (H6) in the TS.\nAlthough FADD DD and TNfn3 have similar stabilities, and appear to have similar folding mechanisms, FADD DD folds significantly faster than TNfn3 (∼ 1000 s- 1 compared to 6 s- 1). This is not unexpected; FADD DD is an all alpha-helical protein with a significantly lower relative contact order than the all-beta TNfn3, and it has been shown that proteins with low contact orders generally have higher folding rate constants.44","divisions":[{"label":"title","span":{"begin":0,"end":54}},{"label":"p","span":{"begin":55,"end":742}},{"label":"p","span":{"begin":743,"end":3096}}],"tracks":[{"project":"2_test","denotations":[{"id":"19362094-10704314-62520533","span":{"begin":182,"end":184},"obj":"10704314"},{"id":"19362094-12515856-62520533","span":{"begin":182,"end":184},"obj":"12515856"},{"id":"19362094-11162123-62520534","span":{"begin":192,"end":194},"obj":"11162123"},{"id":"19362094-18022190-62520535","span":{"begin":201,"end":203},"obj":"18022190"},{"id":"19362094-11377196-62520536","span":{"begin":216,"end":218},"obj":"11377196"},{"id":"19362094-15476825-62520536","span":{"begin":216,"end":218},"obj":"15476825"},{"id":"19362094-9931001-62520537","span":{"begin":248,"end":250},"obj":"9931001"},{"id":"19362094-12515856-62520538","span":{"begin":2246,"end":2248},"obj":"12515856"},{"id":"19362094-9545386-62520539","span":{"begin":3521,"end":3523},"obj":"9545386"}],"attributes":[{"subj":"19362094-10704314-62520533","pred":"source","obj":"2_test"},{"subj":"19362094-12515856-62520533","pred":"source","obj":"2_test"},{"subj":"19362094-11162123-62520534","pred":"source","obj":"2_test"},{"subj":"19362094-18022190-62520535","pred":"source","obj":"2_test"},{"subj":"19362094-11377196-62520536","pred":"source","obj":"2_test"},{"subj":"19362094-15476825-62520536","pred":"source","obj":"2_test"},{"subj":"19362094-9931001-62520537","pred":"source","obj":"2_test"},{"subj":"19362094-12515856-62520538","pred":"source","obj":"2_test"},{"subj":"19362094-9545386-62520539","pred":"source","obj":"2_test"}]}],"config":{"attribute types":[{"pred":"source","value type":"selection","values":[{"id":"2_test","color":"#cd93ec","default":true}]}]}}