Small heat shock proteins (sHSPs) are a class of ATP-independent molecular chaperones that play vital roles in maintaining protein solubility and preventing aberrant protein aggregation. They form highly dynamic, polydisperse oligomeric ensembles and contain long intrinsically disordered regions. Experimental challenges posed by these properties have greatly impeded our understanding of sHSP structure and mechanism of action. Here we characterize interactions between the human sHSP HspB1 (Hsp27) and microtubule-associated protein tau, which is implicated in multiple dementias, including Alzheimer's disease. We show that tau binds both to a well-known binding groove within the structured alpha-crystallin domain (ACD) and to sites within the enigmatic, disordered N-terminal region (NTR) of HspB1. However, only interactions involving the NTR lead to productive chaperone activity, whereas ACD binding is uncorrelated with chaperone function. The tau-binding groove in the ACD also binds short hydrophobic regions within HspB1 itself, and HspB1 mutations that disrupt these intrinsic ACD-NTR interactions greatly enhance chaperone activity toward tau. This leads to a mechanism in which the release of the disordered NTR from a binding groove on the ACD enhances chaperone activity toward tau. The study advances understanding of the mechanisms by which sHSPs achieve their chaperone activity against amyloid-forming clients and how cells defend against pathological tau aggregation. Furthermore, the resulting mechanistic model points to ways in which sHSP chaperone activity may be increased, either by native factors within the cell or by therapeutic intervention.

中文翻译：

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无序结构域的释放增强了 HspB1 伴侣对 tau 蛋白的活性。


小热休克蛋白 (sHSP) 是一类不依赖于 ATP 的分子伴侣，在维持蛋白质溶解度和防止异常蛋白质聚集方面发挥着重要作用。它们形成高度动态的、多分散的寡聚整体，并包含长的本质上无序的区域。这些特性带来的实验挑战极大地阻碍了我们对 sHSP 结构和作用机制的理解。在这里，我们描述了人类 sHSP HspB1 (Hsp27) 和微管相关蛋白 tau 之间的相互作用，该蛋白与多种痴呆症有关，包括阿尔茨海默病。我们发现 tau 既能与结构化 α-晶状体蛋白结构域 (ACD) 内众所周知的结合槽结合，又能与 HspB1 神秘、无序的 N 端区域 (NTR) 内的位点结合。然而，只有涉及 NTR 的相互作用才会产生有效的伴侣活性，而 ACD 结合与伴侣功能不相关。 ACD 中的 tau 结合沟还结合 HspB1 本身内的短疏水区域，而破坏这些内在 ACD-NTR 相互作用的 HspB1 突变极大地增强了伴侣对 tau 的活性。这导致了一种机制，其中无序的 NTR 从 ACD 上的结合槽释放增强了伴侣对 tau 的活性。该研究加深了人们对 sHSP 实现其针对淀粉样蛋白形成客户的伴侣活性的机制以及细胞如何防御病理性 tau 聚集的理解。此外，由此产生的机制模型指出了可以通过细胞内的天然因素或通过治疗干预来增加 sHSP 伴侣活性的方法。