A weakened interface in the P182L variant of HSP27 associated with severe Charcot-Marie-Tooth neuropathy causes aberrant binding to interacting proteins.
A weakened interface in the P182L variant of HSP27 associated with severe Charcot-Marie-Tooth neuropathy causes aberrant binding to interacting proteins.
复制标题
与严重的Charcot-Marie-Tooth神经病相关的HSP27 P182L变异体的界面减弱会导致与相互作用蛋白的异常结合。
DOI：
10.15252/embj.2019103811
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发表时间：
2021-04-15
期刊：
影响因子：
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通讯作者：
Lp Benesch J
中科院分区：
文献类型：
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作者：
Alderson TR;Adriaenssens E;Asselbergh B;Pritišanac I;Van Lent J;Gastall HY;Wälti MA;Louis JM;Timmerman V;Baldwin AJ;Lp Benesch J
HSP 27是一种人分子伴侣，形成大的动态寡聚体，并在细胞稳态的许多方面发挥作用。HSP 27的突变导致Charcot玛丽-图思（CMT）病，这是周围神经系统最常见的遗传性疾病。CMT疾病的一种特别严重的形式是由P182 L突变引发的，该突变位于无序C末端区域的高度保守的IxI/V基序中，该基序与HSP 27的结构化核心结构域弱相互作用。在这里，我们观察到P182 L突变破坏了分子伴侣活性，并显着增加了体内形成的HSP 27寡聚体的大小，包括在从CMT患者来源的干细胞分化的运动神经元中。使用NMR光谱，我们确定P182 L突变降低了HSP 27 IxI/V基序对其自身核心结构域的亲和力，使该结合位点更容易与其他含IxI/V的蛋白质结合。我们鉴定了多种携带IxI/V的蛋白质，由于IxI/V结合位点的可用性增加，这些蛋白质与P182 L变体的结合亲和力更高。我们的研究结果为P182 L突变对HSP 27的影响提供了机制基础，并表明IxI/V基序在调节蛋白质-蛋白质相互作用中起着重要的调节作用。NMR研究定义了P182 L突变如何改变分子内相互作用，以增加HSP 27对许多结合蛋白的可及性，从而损害其在患者细胞来源的运动神经元中的伴侣功能。
HSP27 is a human molecular chaperone that forms large, dynamic oligomers and functions in many aspects of cellular homeostasis. Mutations in HSP27 cause Charcot‐Marie‐Tooth (CMT) disease, the most common inherited disorder of the peripheral nervous system. A particularly severe form of CMT disease is triggered by the P182L mutation in the highly conserved IxI/V motif of the disordered C‐terminal region, which interacts weakly with the structured core domain of HSP27. Here, we observed that the P182L mutation disrupts the chaperone activity and significantly increases the size of HSP27 oligomers formed in vivo, including in motor neurons differentiated from CMT patient‐derived stem cells. Using NMR spectroscopy, we determined that the P182L mutation decreases the affinity of the HSP27 IxI/V motif for its own core domain, leaving this binding site more accessible for other IxI/V‐containing proteins. We identified multiple IxI/V‐bearing proteins that bind with higher affinity to the P182L variant due to the increased availability of the IxI/V‐binding site. Our results provide a mechanistic basis for the impact of the P182L mutation on HSP27 and suggest that the IxI/V motif plays an important, regulatory role in modulating protein–protein interactions. NMR studies define how the P182L mutation alters intramolecular interactions to increase HSP27 accessibility for numerous binding proteins, compromising its chaperone function in patient cell‐derived motor neurons.