Jul 6, 2016

An internal disulfide locks a misfolded aggregation-prone intermediate in cataract-linked mutants of human γD-crystallin

BioRxiv : the Preprint Server for Biology
Eugene SerebryanyEugene I. Shakhnovich


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. Two-chain all-atom simulations predicted that one non-native 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. Specific binding between the extruded ha...Continue Reading

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Mentioned in this Paper

APP protein, human
Amyloid Protein Activity
Hairpin Loop Sequence
Oxidative Stress
Generalized Illness
NEDD8-Activating Enzyme E1 Regulatory Subunit
Mass Spectrometry

About this Paper

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