Dissecting the contributions of β-hairpin tyrosine pairs to the folding and stability of long-lived human γD-crystallins

Nanoscale
Zaixing YangRuhong Zhou

Abstract

Ultraviolet-radiation-induced damage to and aggregation of human lens crystallin proteins are thought to be a significant pathway to age-related cataract. The aromatic residues within the duplicated Greek key domains of γ- and β-crystallins are the main ultraviolet absorbers and are susceptible to direct and indirect ultraviolet damage. The previous site-directed mutagenesis studies have revealed a striking difference for two highly conserved homologous β-hairpin Tyr pairs, at the N-terminal domain (N-td) and C-terminal domain (C-td), respectively, in their contribution to the overall stability of HγD-Crys, but why they behave so differently still remains a mystery. In this paper, we systematically investigated the underlying molecular mechanism and detailed contributions of these two Tyr pairs with large scale molecular dynamics simulations. A series of different tyrosine-to-alanine pair(s) substitutions were performed in either the N-td, the C-td, or both. Our results suggest that the Y45A/Y50A pair substitution in the N-td mainly affects the stability of the N-td itself, while the Y133A/Y138A pair substitution in the C-td leads to a more cooperative unfolding of both N-td and C-td. The stability of motif 2 in the N-td is mai...Continue Reading

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Citations

May 20, 2014·Progress in Biophysics and Molecular Biology·Eugene Serebryany, Jonathan A King
Jun 28, 2015·Biochimica Et Biophysica Acta·Venkata Pulla Rao VendraDorairajan Balasubramanian
Jun 20, 2018·Journal of the American Chemical Society·Hongsuk KangRuhong Zhou

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