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 β-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 β-strand-rich proteins.

中文翻译：

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尖端连接蛋白老化导致相互作用网络减弱，导致听力损失


年龄相关性听力损失（ARHL）是人类的一种常见病症，标志着听力随着年龄的增长而逐渐下降。吸收声音机械张力并维持听力完整性的尖端连接蛋白钙粘蛋白 23 的扰动与 ARHL 相关。在这里，为了寻找 ARHL 的分子起源，我们剖析了 cadherin-23 以及急剧加剧听力损失的突变体 S47P 的构象行为。使用一系列实验和计算方法，我们强调了由于 S47P 突变导致的热力学稳定性较低、氢键网络显着减弱以及 β 链之间的残基间相关性。相关运动的损失不仅导致突变体折叠速度显着减慢两个数量级，而且还导致展开机制相对复杂。因此，我们提出，随着衰老，cadherin-23 内相关运动的丧失可能会引发 ARHL，这种分子特征可能适用于富含 β 链的蛋白质中的其他疾病突变。