The folding mechanism of a β-sheet: the WW domain

Jäger, Markus; Nguyen, Houbi; Crane, Jason C.; Kelly, Jeffery W.; Gruebele, Martin

doi:10.1006/jmbi.2001.4873

Cited by 303 publications

(500 citation statements)

References 65 publications

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“…Pin1 WW domain is reported to be a two-state folder [22]: this is recovered by both the MC and the MF approximations, as can be seen in Fig. 2.…”

Section: Resultsmentioning

confidence: 60%

“…It is remarkable that the barrier separating folded from unfolded conformations is quite flat, especially in the MC case, so that mutations could likely induce relevant changes in its position with just a slight change in the energies, a scenario which is indeed suggested in Ref. [22].…”

Section: Resultsmentioning

confidence: 63%

“…In our computation we set q = 2.31 and regarded ε as an adjustable parameter. We determined it by imposing that the meanfield specific heat exhibits its "collapse" peak in correspondence to the experimental transition temperature T = 332 K [22]. Despite the use of a simple MF approach, we expect that this procedure yields a correct estimate for ε, since the MF is known to reproduce the thermodynamics properties of the Finkelstein model pretty faithfully [20].…”

Section: Methodsmentioning

confidence: 99%

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Analysis of PIN1 WW domain through a simple statistical mechanics model

Bruscolini

Cecconi

2005

Biophysical Chemistry

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We have applied a simple statistical-mechanics Gō-like model to the analysis of the PIN1 WW domain, resorting to Mean Field and Monte Carlo techniques to characterize its thermodynamics, and comparing the results with the wealth of available experimental data. PIN1 WW domain is a 39-residues protein fragment which folds on an antiparallel β-sheet, thus representing an interesting model system to study the behavior of these secondary structure elements. Results show that the model correctly reproduces the two-state behavior of the protein, and also the trends of the experimental φT -values. Moreover, there is a good agreement between Monte Carlo results and the Mean-Field ones, which can be obtained with a substantially smaller computational effort.

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“…Pin1 WW domain is reported to be a two-state folder [22]: this is recovered by both the MC and the MF approximations, as can be seen in Fig. 2.…”

Section: Resultsmentioning

confidence: 60%

Section: Resultsmentioning

confidence: 63%

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Analysis of PIN1 WW domain through a simple statistical mechanics model

Bruscolini

Cecconi

2005

Biophysical Chemistry

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“…For efficient folding, approximate turn structure is likely formed early in the folding pathway to allow for structural collapse, and several studies have characterized the importance of turns to both folding (as folding nuclei) [21][22][23] and stability. 24 We report a comprehensive u-value analysis for each of the 11 turns of FGF-1, involving a total of 44 residue positions within the 140 amino acid FGF-1 protein.…”

Section: Introductionmentioning

confidence: 99%

Experimental support for the foldability–function tradeoff hypothesis: Segregation of the folding nucleus and functional regions in fibroblast growth factor‐1

2012

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The acquisition of function is often associated with destabilizing mutations, giving rise to the stability-function tradeoff hypothesis. To test whether function is also accommodated at the expense of foldability, fibroblast growth factor-1 (FGF-1) was subjected to a comprehensive u-value analysis at each of the 11 turn regions. FGF-1, a b-trefoil fold, represents an excellent model system with which to evaluate the influence of function on foldability: because of its threefold symmetric structure, analysis of FGF-1 allows for direct comparisons between symmetryrelated regions of the protein that are associated with function to those that are not; thus, a structural basis for regions of foldability can potentially be identified. The resulting u-value distribution of FGF-1 is highly polarized, with the majority of positions described as either foldedlike or denatured-like in the folding transition state. Regions important for folding are shown to be asymmetrically distributed within the protein architecture; furthermore, regions associated with function (i.e., heparin-binding affinity and receptor-binding affinity) are localized to regions of the protein that fold after barrier crossing (late in the folding pathway). These results provide experimental support for the foldability-function tradeoff hypothesis in the evolution of FGF-1. Notably, the results identify the potential for folding redundancy in symmetric protein architecture with important implications for protein evolution and design.

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“…However, knowledge of the mechanical and structural dynamics within b-sheet assemblies such as amyloid fibrils remains limited. Early assumptions that bsheet assemblies, which include amyloid fibrils, occupy a global minimum of free energy that is lower than that of the native state [3] led to a greater emphasis on the understanding and inhibition of amyloid formation, rather than that of amyloid dissociation and clearance. Despite the stability of bsheet-rich amyloid fibrils against proteases, acids, and chemical denaturants, increasing evidence from human [4] and in vitro studies indicates that a dynamic structure exists within amyloid fibrils and suggests that the process of amyloid formation is reversible.…”

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confidence: 99%

Disruption of Amyloid‐Derived Peptide Assemblies through the Controlled Induction of a β‐Sheet to α‐Helix Transformation: Application of the Switch Concept

et al. 2007

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-Sheet-based assemblies have attracted a considerable amount of attention from researchers of various disciplines because of their association with a variety of diseases and their emerging potential in material sciences and biotechnology. [1] Protein misfolding and self-assembly into highly ordered b-sheet-rich fibrillar assemblies that are known as amyloid fibrils are common features of a growing class of systemic and neurodegenerative diseases, which include Alzheimer s, Parkinson s, and Huntington s diseases, senile systemic amyloidoses, as well as type II diabetes. [2] Although there is strong evidence that implicates amyloid formation in the pathogenesis of these diseases, the precise mechanisms of amyloid formation and clearance in vivo, as well as the structural basis of amyloid toxicity, remain unknown. The lack of tools to monitor and/or control the initial structural transitions associated with protein misfolding, amyloid formation, and/or dissociation is the main cause of this gap in knowledge. Significant efforts have been devoted to study proteins and small peptides that self-assemble into amyloidlike fibrillar structures as model systems to investigate amyloid formation or to generate materials with interesting physical properties. However, knowledge of the mechanical and structural dynamics within b-sheet assemblies such as amyloid fibrils remains limited. Early assumptions that bsheet assemblies, which include amyloid fibrils, occupy a global minimum of free energy that is lower than that of the native state [3] led to a greater emphasis on the understanding and inhibition of amyloid formation, rather than that of amyloid dissociation and clearance. Despite the stability of bsheet-rich amyloid fibrils against proteases, acids, and chemical denaturants, increasing evidence from human [4] and in vitro studies indicates that a dynamic structure exists within amyloid fibrils and suggests that the process of amyloid formation is reversible. [5a,b] These findings, along with the fact that strategies aimed at the destabilization of amyloid fibrils and/or the acceleration of their clearance seem to reverse the disease phenotype, [6][7] suggest that a detailed understanding of the stability and dynamic behavior of amyloid fibrils is of critical importance to the development of therapeutic strategies for amyloid diseases.Our research group has previously shown [8][9][10] that the incorporation of molecular switches into polypeptides, based on an in situ intramolecular O!N acyl group migration, [11] allows for the controlled induction or reversal of secondary structural transitions [12a,b,c] and self-assembly of small peptide chains. Herein we describe a switch peptide that is designed to disrupt amyloid-like b-sheet assemblies through the controlled induced transition from a b-sheet to an a-helix structure (Figure 1). The experimental results illustrate the potential of switch peptides as a tool to investigate the structural dynamics of amyloid fibrils, to provide an insight into the structural basis o...

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The folding mechanism of a β-sheet: the WW domain

Cited by 303 publications

References 65 publications

Analysis of PIN1 WW domain through a simple statistical mechanics model

Analysis of PIN1 WW domain through a simple statistical mechanics model

Experimental support for the foldability–function tradeoff hypothesis: Segregation of the folding nucleus and functional regions in fibroblast growth factor‐1

Disruption of Amyloid‐Derived Peptide Assemblies through the Controlled Induction of a β‐Sheet to α‐Helix Transformation: Application of the Switch Concept

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