Molecular Biophysics Graduate Program, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Center for Alzheimer's and Neurodegenerative Diseases, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Nat Commun. 2021 Feb 11;12(1):946. doi: 10.1038/s41467-021-21147-x.
The Hsp40/Hsp70 chaperone families combine versatile folding capacity with high substrate specificity, which is mainly facilitated by Hsp40s. The structure and function of many Hsp40s remain poorly understood, particularly oligomeric Hsp40s that suppress protein aggregation. Here, we used a combination of biochemical and structural approaches to shed light on the domain interactions of the Hsp40 DnaJB8, and how they may influence recruitment of partner Hsp70s. We identify an interaction between the J-Domain (JD) and C-terminal domain (CTD) of DnaJB8 that sequesters the JD surface, preventing Hsp70 interaction. We propose a model for DnaJB8-Hsp70 recruitment, whereby the JD-CTD interaction of DnaJB8 acts as a reversible switch that can control the binding of Hsp70. These findings suggest that the evolutionarily conserved CTD of DnaJB8 is a regulatory element of chaperone activity in the proteostasis network.
Hsp40/Hsp70 伴侣蛋白家族兼具多功能的折叠能力和高底物特异性，这主要得益于 Hsp40。许多 Hsp40 的结构和功能仍知之甚少，特别是具有抑制蛋白聚集功能的寡聚 Hsp40。在这里，我们采用了生化和结构方法的组合，阐明了 Hsp40 DnaJB8 的结构域相互作用，以及它们如何影响伴侣 Hsp70 的募集。我们发现 DnaJB8 的 J 结构域（JD）和 C 末端结构域（CTD）之间存在相互作用，该相互作用将 JD 表面隔离，从而阻止 Hsp70 与之相互作用。我们提出了一个 DnaJB8-Hsp70 募集的模型，其中 DnaJB8 的 JD-CTD 相互作用可以作为一个可逆开关，控制 Hsp70 的结合。这些发现表明，DnaJB8 的进化上保守的 CTD 是蛋白质稳态网络中伴侣活性的调节元件。
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