Separating Instability from Aggregation Propensity in γS-crystallin Variants

Overview

Journal Biophys J

Publisher Cell Press

Specialty Biophysics

Date 2011 Jan 20

PMID 21244846

Citations 37

Authors

William D Brubaker

J Alfredo Freites

Kory J Golchert

Rebecca A Shapiro

Vasilios Morikis

Douglas J Tobias

Rachel W Martin

Affiliations

Soon will be listed here.

Abstract

Molecular dynamics (MD) simulations, circular dichroism (CD), and dynamic light scattering (DLS) measurements were used to investigate the aggregation propensity of the eye-lens protein γS-crystallin. The wild-type protein was investigated along with the cataract-related G18V variant and the symmetry-related G106V variant. The MD simulations suggest that local sequence differences result in dramatic differences in dynamics and hydration between these two apparently similar point mutations. This finding is supported by the experimental measurements, which show that although both variants appear to be mostly folded at room temperature, both display increased aggregation propensity. Although the disease-related G18V variant is not the most strongly destabilized, it aggregates more readily than either the wild-type or the G106V variant. These results indicate that γS-crystallin provides an excellent model system for investigating the role of dynamics and hydration in aggregation by locally unfolded proteins.

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