HSP40 proteins use class-specific regulation to drive HSP70 functional diversity
HSP40 proteins use class-specific regulation to drive HSP70 functional diversity
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DOI：
10.1038/s41586-020-2906-4
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发表时间：
2020-11-11
期刊：
影响因子：
64.8
通讯作者：
Rosenzweig, Rina
中科院分区：
文献类型：
--
作者：
Faust, Ofrah;Abayev-Avraham, Meital;Rosenzweig, Rina
B 类 J 结构域蛋白对 HSP70 的结合和激活受到自动抑制调节机制的控制，该机制控制底物靶向 HSP70，并且是淀粉样纤维解聚所必需的。普遍存在的热休克蛋白 70 (HSP70) 家族由 ATP 依赖性分子伴侣组成，其执行多种细胞功能，几乎影响蛋白质的所有方面 从合成到降解的生命周期(1-3)。实现如此广泛的功能需要精确调节 HSP70 活性。 HSP40 家族的蛋白质（也称为 J 结构域蛋白 (JDP)）在此过程中发挥着关键作用，它们可以预先选择要转移至其 HSP70 伙伴的底物，并刺激 HSP70 的 ATP 水解，从而实现稳定的底物结合 (3,4)。在人类中，JDP 构成了一个庞大而多样化的家族，拥有 40 多个不同的成员 (2)，其底物选择性以及客户结合域的性质和数量各不相同 (5)。在这里，我们表明 JDP 在与 HSP70 伴侣的相互作用方面也存在根本差异。使用核磁共振波谱 (6,7)，我们发现主要 B 类 JDP 受到其他类中不存在的自动抑制机制的调节。尽管在所有 JDP 中，特征性 J 结构域的相互作用负责 HSP70 的激活，但在 DNAJB1 中，该结构域中的 HSP70 结合位点本质上被相邻的富含甘氨酸-苯丙氨酸的区域阻断，这种抑制可以在 DNAJB1 上的第二个位点与 HSP70 C 末端尾部相互作用时释放。这种控制底物靶向 HSP70 的调节对于 HSP70-DNAJB1 解聚淀粉样蛋白纤维至关重要，这说明了为什么没有其他类别的 JDP 可以替代 B 类的这一功能。此外，这个调控层控制 JDP 共伴侣的功能特异性及其与 HSP70 的相互作用，可能是 HSP70 广泛细胞功能的关键。
The binding and activation of HSP70 by class B J-domain proteins is subject to an autoinhibitory regulatory mechanism that controls substrate targeting to HSP70 and is required for the disaggregation of amyloid fibres.The ubiquitous heat shock protein 70 (HSP70) family consists of ATP-dependent molecular chaperones, which perform numerous cellular functions that affect almost all aspects of the protein life cycle from synthesis to degradation(1-3). Achieving this broad spectrum of functions requires precise regulation of HSP70 activity. Proteins of the HSP40 family, also known as J-domain proteins (JDPs), have a key role in this process by preselecting substrates for transfer to their HSP70 partners and by stimulating the ATP hydrolysis of HSP70, leading to stable substrate binding(3,4). In humans, JDPs constitute a large and diverse family with more than 40 different members(2), which vary in their substrate selectivity and in the nature and number of their client-binding domains(5). Here we show that JDPs can also differ fundamentally in their interactions with HSP70 chaperones. Using nuclear magnetic resonance spectroscopy(6,7) we find that the major class B JDPs are regulated by an autoinhibitory mechanism that is not present in other classes. Although in all JDPs the interaction of the characteristic J-domain is responsible for the activation of HSP70, in DNAJB1 the HSP70-binding sites in this domain are intrinsically blocked by an adjacent glycine-phenylalanine rich region-an inhibition that can be released upon the interaction of a second site on DNAJB1 with the HSP70 C-terminal tail. This regulation, which controls substrate targeting to HSP70, is essential for the disaggregation of amyloid fibres by HSP70-DNAJB1, illustrating why no other class of JDPs can substitute for class B in this function. Moreover, this regulatory layer, which governs the functional specificities of JDP co-chaperones and their interactions with HSP70s, could be key to the wide range of cellular functions of HSP70.