The Structure of the Transition State for Folding of Chymotrypsin Inhibitor 2 Analysed by Protein Engineering Methods: Evidence for a Nucleation-condensation Mechanism for Protein Folding

Itzhaki, Laura S.; Otzen, Daniel E.; Fersht, Alan R.

doi:10.1006/jmbi.1995.0616

Cited by 732 publications

(639 citation statements)

References 59 publications

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“…In a few studies that addressed the global connectivity of sequence space, it has been observed further that neutral nets for different folded structures are interconnected to form a dominant 'supernet' covering most of the sequence space [298,303,324] in a manner similar to that envisioned by Maynard Smith [336]. Consistent with experiment [139][140][141][142] ( §2.4.2), mutations on encoding sequences often result in sequences encoding for the same structure [137,297,305], especially if the mutation site is on the surface of the folded protein [297]. In other words, many sequences are stable against mutation, a property referred to as mutational robustness [306].…”

Section: Predictions and Rationalizationsmentioning

confidence: 55%

Biophysics of protein evolution and evolutionary protein biophysics

Sikosek

Chan

2014

J. R. Soc. Interface.

213

196

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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: Predictions and Rationalizationsmentioning

confidence: 55%

Biophysics of protein evolution and evolutionary protein biophysics

Sikosek

Chan

2014

J. R. Soc. Interface.

213

196

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“…In analogy to classical folding of globular proteins, the reaction occurs in a highly cooperative manner, without accumulation of partly folded intermediates and with a transition state that resembles a slightly distorted version of the native state (29). We observe folding to be triggered by the formation of two nuclei located at the N-and C termini of c-Myb*, with some minor misfolding defects at the center of the helix.…”

Section: Resultsmentioning

confidence: 71%

“…In the case of protein folding, it has been suggested that the linearity of the LFER plot is distinctive of the so-called nucleation-condensation mechanism, whereby the transition state resembles a distorted version of the native state and the whole protein collapses around a weakly formed nucleus (29). Comparative analysis of nearly all Φ-values reported to date revealed that the α-value in protein folding is robust and, for nearly all proteins investigated, α is about 0.36 (30).…”

Section: An Ordered Transition State As a Signature Of Geometrical Prmentioning

confidence: 99%

Structure of the transition state for the binding of c-Myb and KIX highlights an unexpected order for a disordered system

Giri

Morrone

Toto

et al. 2013

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

100

133

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A classical dogma of molecular biology dictates that the 3D structure of a protein is necessary for its function. However, a considerable fraction of the human proteome, although functional, does not adopt a defined folded state under physiological conditions. These intrinsically disordered proteins tend to fold upon binding to their partners with a molecular mechanism that is elusive to experimental characterization. Indeed, although many hypotheses have been put forward, the functional role (if any) of disorder in these intrinsically denatured systems is still shrouded in mystery. Here, we characterize the structure of the transition state of the binding-induced folding in the reaction between the KIX domain of the CREB-binding protein and the transactivation domain of c-Myb. The analysis, based on the characterization of a series of conservative site-directed mutants, reveals a very high content of native-like structure in the transition state and indicates that the recognition between KIX and c-Myb is geometrically precise. The implications of our results in the light of previous work on intrinsically unstructured systems are discussed.kinetics | mutagenesis | protein folding

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“…Several other small single domain proteins were later shown to fold in a similar way [3]. The two state mechanism provided the basis for a nucleation-condensation mechanism, with folding through simultaneous formation of secondary and tertiary structure centered around a small folding nucleus [4,5]. Recent work on the homeodomain superfamily [6,7] and on a PDZ domain [8], led to the view that the framework and nucleation-condensation models represent extreme manifestation of an underlying common mechanism and that proteins may appear to fold by either the nucleation-condensation or framework mechanism depending on the inherent stability of their secondary structure elements [7,9].…”

Section: Introductionmentioning

confidence: 99%

Identification and characterization of protein folding intermediates

Gianni

Ivarsson

Jemth

et al. 2007

Biophysical Chemistry

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In order to understand the mechanism by which a polypeptide chain folds into its functionally active native state it is necessary to characterize in detail all the species accumulated along the pathway.The elusive nature of protein folding intermediates poses their identification and characterization as an extremely difficult task in the protein folding field. In the case of small single domain proteins, the direct measurement of the thermodynamics and structural parameters of protein folding intermediates has provided new insights on the nature of the forces involved in the stabilization of nascent protein structures. Here we summarize some of the experimental approaches aimed at the detection and characterization of folding intermediates along with a discussion of some general structural features emerging from these studies.

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The Structure of the Transition State for Folding of Chymotrypsin Inhibitor 2 Analysed by Protein Engineering Methods: Evidence for a Nucleation-condensation Mechanism for Protein Folding

Cited by 732 publications

References 59 publications

Biophysics of protein evolution and evolutionary protein biophysics

Biophysics of protein evolution and evolutionary protein biophysics

Structure of the transition state for the binding of c-Myb and KIX highlights an unexpected order for a disordered system

Identification and characterization of protein folding intermediates

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