HspB1 phosphorylation regulates its intramolecular dynamics and mechanosensitive molecular chaperone interaction with filamin C
HspB1 phosphorylation regulates its intramolecular dynamics and mechanosensitive molecular chaperone interaction with filamin C
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DOI：
10.1126/sciadv.aav8421
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发表时间：
2019-05-01
期刊：
影响因子：
13.6
通讯作者：
Benesch, Justin L. P.
中科院分区：
文献类型：
--
作者：
Collier, Miranda P.;Alderson, T. Reid;Benesch, Justin L. P.
机械力引起的蛋白质构象变化支撑着多种生理功能，典型的就是肌肉收缩机制。肌动蛋白结合蛋白细丝蛋白 C (FLNC) 的突变与肌肉骨骼病理相关，其特征是生物力学特性改变，有时甚至是聚集。 HspB1 是一种丰富的分子伴侣，普遍存在于横纹肌中，在响应包括机械应力在内的信号时被磷酸化。我们报告了三种生物力学应激小鼠模型中这两种蛋白的相互作用和上调，其中 HspB1 被磷酸化，FLNC 定位于承载位点。我们展示了磷酸化如何导致 HspB1 磷酸位点周围残基的暴露增加，从而促进它们与 FLNC 的紧凑多域区域结合，该区域被认为具有机械传感功能。 FLNC 的定向展开表明其延伸轨迹受到 HspB1 磷酸化区域的调节。这可能代表了一种翻译后调节的伴侣-客户保护机制，针对机械应力期间的过度伸展。
Mechanical force-induced conformational changes in proteins underpin a variety of physiological functions, typified in muscle contractile machinery. Mutations in the actin-binding protein filamin C (FLNC) are linked to musculoskeletal pathologies characterized by altered biomechanical properties and sometimes aggregates. HspB1, an abundant molecular chaperone, is prevalent in striated muscle where it is phosphorylated in response to cues including mechanical stress. We report the interaction and up-regulation of both proteins in three mouse models of biomechanical stress, with HspB1 being phosphorylated and FLNC being localized to load-bearing sites. We show how phosphorylation leads to increased exposure of the residues surrounding the HspB1 phosphosite, facilitating their binding to a compact multidomain region of FLNC proposed to have mechanosensing functions. Steered unfolding of FLNC reveals that its extension trajectory is modulated by the phosphorylated region of HspB1. This may represent a posttranslationally regulated chaperone-client protection mechanism targeting over-extension during mechanical stress.