期刊
BIOCHEMICAL JOURNAL
卷 478, 期 1, 页码 121-134出版社
PORTLAND PRESS LTD
DOI: 10.1042/BCJ20200799
关键词
-
资金
- DBT/Wellcome Trust India Alliance Fellowship [IA/I/15/1/501817]
Research has shown that age-related hearing loss is associated with the S47P mutation in the cadherin-23 protein, leading to decreased stability and loss of correlated motions. These changes not only result in significantly slower folding in the mutant, but also affect the complex unfolding mechanism.
Age-related hearing loss (ARHL) is a common condition in humans marking the gradual decrease in hearing with age. Perturbations in the tip-link protein cadherin-23 that absorbs the mechanical tension from sound and maintains the integrity of hearing is associated with ARHL. Here, in search of molecular origins for ARHL, we dissect the conformational behavior of cadherin-23 along with the mutant S47P that progresses the hearing loss drastically. Using an array of experimental and computational approaches, we highlight a lower thermodynamic stability, significant weakening in the hydrogen-bond network and inter-residue correlations among beta-strands, due to the S47P mutation. The loss in correlated motions translates to not only a remarkable two orders of magnitude slower folding in the mutant but also to a proportionately complex unfolding mechanism. We thus propose that loss in correlated motions within cadherin-23 with aging may trigger ARHL, a molecular feature that likely holds true for other disease-mutations in beta-strand-rich proteins.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据