The Human W42R γD-Crystallin Mutant Structure Provides a Link between Congenital and Age-related Cataracts*

Ji, Fangling; Jung, Jinwon; Koharudin, Leonardus M. I.; Gronenborn, Angela M.

doi:10.1074/jbc.m112.416354

Cited by 53 publications

(99 citation statements)

References 46 publications

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“…An increasing number of neurodegenerative and other varieties of prion and amyloid diseases are now known to be caused by misfolded structures (different 'native' structures) or by aggregation/oligomerization of intermediate conformational states, with propensity for misfolding increased by certain mutations [87,89] (figure 3). Cataracts in the human eye are also found to be caused by accumulation of misfolded proteins [90] and associated with mutations that led to abnormal folding behaviour [91,92]. As exemplified by the mouse prion protein and consistent with the general observation of evolutionary selection for kinetic stability [81], the folding and maintenance of the non-disease folded form of some of the pertinent proteins (the misfolded forms of which are implicated in diseases) is under kinetic rather than thermodynamic control [93].…”

Section: Biophysical Consequences Of Protein Mutations 21 Mutationamentioning

confidence: 89%

Biophysics of protein evolution and evolutionary protein biophysics

Sikosek

Chan

2014

J. R. Soc. Interface.

214

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: Biophysical Consequences Of Protein Mutations 21 Mutationamentioning

confidence: 89%

Biophysics of protein evolution and evolutionary protein biophysics

Sikosek

Chan

2014

J. R. Soc. Interface.

214

207

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“…In line with the multiple causality of the disease, several distinct biochemical perturbations in vitro have been shown to cause crystallin aggregation (54,(62)(63)(64). Cataract-associated point mutations, especially ones mimicking in vivo chemical modifications, have been highly useful in dissecting the mechanism of aggregation (21,39,51) and developing interventions to modify it (65). Synergistic effects are likely among the various modes of modification or damage.…”

Section: Discussionmentioning

confidence: 99%

An Internal Disulfide Locks a Misfolded Aggregation-Prone Intermediate in Cataract-Linked Mutants of Human Gamma-D Crystallin

Serebryany

Woodard

Adkar

et al. 2017

Biophysical Journal

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Considerable mechanistic insight has been gained into amyloid aggregation; however, a large class of non-amyloid protein aggregates are considered "amorphous," and in most cases little is known about their mechanisms. Amorphous aggregation of γ-crystallins in the eye lens causes a widespread disease of aging, cataract. We combined simulations and experiments to study the mechanism of aggregation of two γD-crystallin mutants, W42R and W42Q -the former a congenital cataract mutation, and the latter a mimic of age-related oxidative damage. We found that formation of an internal disulfide was necessary and sufficient for aggregation under physiological conditions. Twochain all-atom simulations predicted that one nonnative disulfide in particular, between Cys32 and Cys41, was likely to stabilize an unfolding intermediate prone to intermolecular interactions. Mass spectrometry and mutagenesis experiments confirmed the presence of this bond in the aggregates and its necessity for oxidative aggregation under physiological conditions in vitro. Mining the simulation data linked formation of this disulfide to extrusion of the N-terminal β-hairpin and rearrangement of the native β-sheet topology.

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“…After 2 h, all protein was digested, but E. a-BDH resisted to the trypsin digestion up to 36 h incubation (data not shown) at 37 • C. These results suggest that the change of protein structure by mutation may cause its sensitivity to trypsin digestion. In fact, Ji et al have reported similar proteolytic susceptibility phenomenon on human crystallin mutant because of a partially unfolded species [23]. In our case, nevertheless, it is possible that the mutation induced the conformational change of D194G B. s-BDH.…”

Section: Structure Of D194g B S-bdhmentioning

confidence: 73%