J-domain proteins (JDPs) constitute a large family of molecular chaperones that bind a broad spectrum of substrates, targeting them to Hsp70, thus determining the specificity of and activating the entire chaperone functional cycle. The malfunction of JDPs is therefore inextricably linked to myriad human disorders. Here, we uncover a unique mechanism by which chaperones recognize misfolded clients, present in human class A JDPs. Through a newly identified β-hairpin site, these chaperones detect changes in protein dynamics at the initial stages of misfolding, prior to exposure of hydrophobic regions or large structural rearrangements. The JDPs then sequester misfolding-prone proteins into large oligomeric assemblies, protecting them from aggregation. Through this mechanism, class A JDPs bind destabilized p53 mutants, preventing clearance of these oncoproteins by Hsp70-mediated degradation, thus promoting cancer progression. Removal of the β-hairpin abrogates this protective activity while minimally affecting other chaperoning functions. This suggests the class A JDP β-hairpin as a highly specific target for cancer therapeutics.

J 结构域蛋白 (JDP) 构成了一个分子伴侣大家族，可结合广谱底物，将其靶向 Hsp70，从而确定整个伴侣功能循环的特异性并激活整个伴侣功能循环。因此，JDP 的故障与多种人类疾病有着千丝万缕的联系。在这里，我们发现了一种独特的机制，伴侣可以通过这种机制识别人类 A 类 JDP 中存在的错误折叠的客户。通过新识别的 β-发夹位点，这些伴侣在错误折叠的初始阶段、疏水区域暴露或大的结构重排之前检测蛋白质动力学的变化。然后，JDP 将容易错误折叠的蛋白质隔离到大型寡聚体组装体中，保护它们免于聚集。通过这种机制，A 类 JDP 结合不稳定的 p53 突变体，防止 Hsp70 介导的降解清除这些癌蛋白，从而促进癌症进展。去除β-发夹会消除这种保护活性，同时对其他陪伴功能的影响最小。这表明 A 类 JDP β-发夹是癌症治疗的高度特异性靶标。