Release of a disordered domain enhances HspB1 chaperone activity toward tau
Release of a disordered domain enhances HspB1 chaperone activity toward tau
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DOI：
10.1073/pnas.1915099117
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发表时间：
2020-02-11
影响因子：
11.1
通讯作者：
Klevit, Rachel E.
中科院分区：
文献类型：
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作者：
Baughman, Hannah E. R.;Pham, Thanh-Hau T.;Klevit, Rachel E.
小分子热休克蛋白（Small heat shock proteins，sHSPs）是一类不依赖ATP的分子伴侣，在维持蛋白质溶解性和防止蛋白质异常聚集方面发挥重要作用。它们形成高度动态、多分散的低聚物系综，并含有长的内在无序区域。这些性质所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 HspB 1（Hsp 27）和微管相关蛋白tau之间的相互作用，该蛋白与多种痴呆症（包括阿尔茨海默病）有关。我们发现，tau蛋白结合到一个众所周知的结合槽内的结构化α-晶体蛋白结构域（ACD）和网站内的神秘的，无序的N-末端区域（NTR）的HspB 1。然而，只有涉及NTR的相互作用导致生产性伴侣活性，而ACD结合与伴侣功能无关。ACD中的tau结合沟也结合HspB 1自身内的短疏水区域，并且破坏这些固有ACD-NTR相互作用的HspB 1突变极大地增强了针对tau的分子伴侣活性。这导致了一种机制，其中无序NTR从ACD上的结合沟中释放增强了对tau的伴侣活性。该研究促进了对sHSP实现其针对淀粉样蛋白形成客户的伴侣活性以及细胞如何防御病理性tau聚集的机制的理解。此外，所得到的机制模型指出，sHSP伴侣活性可以增加的方式，无论是通过细胞内的天然因素或通过治疗干预。
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.