The Highly Cooperative Folding of Small Naturally Occurring Proteins Is Likely the Result of Natural Selection

Watters, Alexander L.; Deka, Pritilekha; Corrent, Colin; Callender, David R.; Varani, Gabriele; Sosnick, Tobin R.; Baker, David

doi:10.1016/j.cell.2006.12.042

Cited by 134 publications

(190 citation statements)

References 65 publications

(84 reference statements)

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“…It shows that the tendency to misfold does not necessarily diminish with increasing native stability: despite the high native stability of Top7, its folding kinetics is complex, probably involving multiple kinetic traps [154,155]. Theoretical considerations indicate that the lack of two-state-like behaviour of Top7 is probably caused more fundamentally by its peculiar native structure, more so than the fact that it is an artificially designed protein that did not undergo natural selection [156].…”

Section: Reconciling Evolutionary Selection For Stability With Marginmentioning

confidence: 99%

Biophysics of protein evolution and evolutionary protein biophysics

Sikosek

Chan

2014

J. R. Soc. Interface.

224

207

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The study of molecular evolution at the level of protein-coding genes often entails comparing large datasets of sequences to infer their evolutionary relationships. Despite the importance of a protein's structure and conformational dynamics to its function and thus its fitness, common phylogenetic methods embody minimal biophysical knowledge of proteins. To underscore the biophysical constraints on natural selection, we survey effects of protein mutations, highlighting the physical basis for marginal stability of natural globular proteins and how requirement for kinetic stability and avoidance of misfolding and misinteractions might have affected protein evolution. The biophysical underpinnings of these effects have been addressed by models with an explicit coarse-grained spatial representation of the polypeptide chain. Sequence-structure mappings based on such models are powerful conceptual tools that rationalize mutational robustness, evolvability, epistasis, promiscuous function performed by 'hidden' conformational states, resolution of adaptive conflicts and conformational switches in the evolution from one protein fold to another. Recently, protein biophysics has been applied to derive more accurate evolutionary accounts of sequence data. Methods have also been developed to exploit sequence-based evolutionary information to predict biophysical behaviours of proteins. The success of these approaches demonstrates a deep synergy between the fields of protein biophysics and protein evolution.

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Section: Reconciling Evolutionary Selection For Stability With Marginmentioning

confidence: 99%

Biophysics of protein evolution and evolutionary protein biophysics

Sikosek

Chan

2014

J. R. Soc. Interface.

224

207

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“…Caching it inside a helix likely promotes metastable nonnative β-contacts between the two terminal hairpins, slowing down the folding. This may be one of the reasons for the slow and multiphase folding of Top7 observed in recent experiments (5). Our hypothesis could be tested through mutation experiments focusing on residues in Top7 that correspond to the N terminus of the CFr sequence.…”

Section: Resultsmentioning

confidence: 99%

“…The C-terminal hairpin is formed next (3), often away from the helix, before rearranging in a native-like position relative to the helix (4). The helix partially unfolds (5), and the released residues join with the hairpin to complete the native structure (6). Fig.…”

Section: Resultsmentioning

confidence: 99%

Simulation of Top7-CFr: A transient helix extension guides folding

Mohanty

Meinke

Zimmermann

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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Protein structures often feature β-sheets in which adjacent β-strands have large sequence separation. How the folding process orchestrates the formation and correct arrangement of these strands is not comprehensively understood. Particularly challenging are proteins in which β-strands at the N and C termini are neighbors in a β-sheet. The N-terminal β-strand is synthesized early on, but it can not bind to the C terminus before the chain is fully synthesized. During this time, there is a danger that the β-strand at the N terminus interacts with nearby molecules, leading to potentially harmful aggregates of incompletely folded proteins. Simulations of the C-terminal fragment of Top7 show that this risk of misfolding and aggregation can be avoided by a "caching" mechanism that relies on the "chameleon" behavior of certain segments.protein folding | all-atom simulation | folding mechanism | chameleon segment | nonnative intermediates S tructure and function of proteins are determined by their amino acid sequence. How proteins find their functional native form is a long-standing question (1-3). Protein synthesis is directional from the N to the C terminus. In proteins with end-toend β-sheets, there is a danger that the N-terminal strand binds to nearby molecules or other parts of the chain, as the strand cannot bind to the C-terminal strand until the molecule is fully synthesized. Misfolding and aggregation may be the consequence. In our simulations, the N terminus of fragment Glu-2-Leu-50 of the 59-residue CFr (Protein Data Bank ID code 2GJH) (4) avoids the risk of misfolding by growing first into a non-native extension of an existing α-helix. Only after the other structural elements have formed and correctly assembled, does the N terminus unfold and attach to the C-terminal β-sheet as its last closing strand. We speculate that such a temporary caching of β-strands is a common mechanism that eases folding and hinders aggregation.The C-terminal fragment (CFr) (5) of the designed protein Top7 (6) forms a stable homodimer, whose secondary structure remains nearly unchanged up to 98 • C and high concentrations of denaturant (4). It is a model for small fast-folding proteins with complex topology and diverse secondary structure elements (see Fig. 1). Such proteins often have long-distance (in sequence) contacts between β-strands. Unlike helix contacts, these depend on the conformation of a large segment between the strands. It is unlikely that these contacts form before the intermediate segment has folded, as this would lead to a large entropic cost, or even interfere with the folding of the connecting segment. For slowfolding proteins, one can conjecture a "backtracking" mechanism (7) where folding succeeds only after breaking of prematurely formed β-contacts. In this study, we explore in silico the behavior of fast-folding proteins, as computational approaches (8, 9) can resolve details of folding that are beyond the reach of experiments. Results and DiscussionWe find that the CFr monomer folds to a native-like conform...

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“…In a recent study, it was suggested that the cooperativity of the folding reaction is the result of natural selection 39 . It is intriguing that AK e uses cooperative unfolding/refolding to accommodate a large-scale conformational change during catalysis.…”

mentioning

confidence: 99%

Overlap between folding and functional energy landscapes for adenylate kinase conformational change

2010

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Enzyme function is often dependent on fluctuations between inactive and active structural ensembles. Adenylate kinase isolated from Escherichia coli (AK e ) is a small phosphotransfer enzyme in which interconversion between inactive (open) and active (closed) conformations is rate limiting for catalysis. AK e has a modular three-dimensional architecture with two flexible substrate-binding domains that interact with the substrates AmP, ADP and ATP. Here, we show by using a combination of biophysical and mutagenic approaches that the interconversion between open and closed states of the ATP-binding subdomain involves partial subdomain unfolding/refolding in an otherwise folded enzyme. These results provide a novel and, possibly general, molecular mechanism for the switch between open and closed conformations in AK e .

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The Highly Cooperative Folding of Small Naturally Occurring Proteins Is Likely the Result of Natural Selection

Cited by 134 publications

References 65 publications

Biophysics of protein evolution and evolutionary protein biophysics

Biophysics of protein evolution and evolutionary protein biophysics

Simulation of Top7-CFr: A transient helix extension guides folding

Overlap between folding and functional energy landscapes for adenylate kinase conformational change

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