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. 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.

中文翻译：

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HSP40 蛋白使用类特异性调节来驱动 HSP70 功能多样性

无处不在的热休克蛋白 70 (HSP70) 家族由依赖于 ATP 的分子伴侣组成，它们执行多种细胞功能，影响从合成到降解的蛋白质生命周期的几乎所有方面 1 – 3。实现这种广泛的功能需要对 HSP70 活性进行精确调节。HSP40 家族的蛋白质，也称为 J 结构域蛋白 (JDP)，通过预选底物以转移到其 HSP70 伙伴并刺激 HSP70 的 ATP 水解，从而导致稳定的底物结合 3、4，从而在该过程中发挥关键作用. 在人类中，JDP 构成了一个庞大而多样的家族，拥有 40 多个不同的成员 2，它们的底物选择性以及客户端绑定域 5 的性质和数量各不相同。在这里，我们表明 JDP 在与 HSP70 伴侣的相互作用方面也可能存在根本性的不同。使用核磁共振波谱 6 , 7 我们发现主要的 B 类 JDP 受其他类中不存在的自身抑制机制的调节。尽管在所有 JDP 中，特征 J 结构域的相互作用是激活 HSP70 的原因，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——一种抑制作用可以在DNAJB1 上第二个位点与 HSP70 C 端尾部的相互作用。该调节控制底物靶向 HSP70，对于 HSP70-DNAJB1 对淀粉样蛋白纤维的分解至关重要，这说明了为什么没有其他类别的 JDP 可以替代 B 类在此功能中的作用。而且，这一调控层控制着 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。B 类 J 结构域蛋白对 HSP70 的结合和激活受自身抑制调节机制的影响，该机制控制底物靶向 HSP70，并且是淀粉样纤维分解所必需的。