Journal Article

Regulatory inter-domain interactions influence Hsp70 recruitment to the DnaJB8 chaperone

Vaquer-Alicea, Jaime, Matlahov, Irina, van der Wel, Patrick C. A., Bali, Sofia, Joachimiak, Lukasz A., Ryder, Bryan D.

2021

Overview

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. The Hsp70/Hsp40 system plays an important role in maintaining cellular proteostasis but so far it is not well understood how Hsp70 proteins are recruited to specific Hsp40 co-chaperones. Here, the authors combine biochemical and biophysical approaches to characterise the oligomeric mammalian Hsp40 DnaJB8. They identify an intra-oligomer DnaJB8 interaction between the N-terminal J-Domain and the C-terminal domain that occludes the J-Domain surface that binds Hsp70 and propose a model for DnaJB8-Hsp70 recruitment.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 101/58 / 101/6 / 631/45/470 / 631/45/535/1267 / 631/45/535/878 / 631/45/612/1981 / 82/16 / Biological Evolution / Chaperones / Domains / HEK293 Cells / HSP40 Heat-Shock Proteins - chemistry / HSP40 Heat-Shock Proteins - genetics / HSP40 Heat-Shock Proteins - metabolism / Hsp40 protein / HSP70 Heat-Shock Proteins - chemistry / HSP70 Heat-Shock Proteins - metabolism / Hsp70 protein / Humanities and Social Sciences / Humans / Models, Molecular / Molecular Chaperones - chemistry / Molecular Chaperones - genetics / Molecular Chaperones - metabolism / multidisciplinary / Nerve Tissue Proteins - chemistry / Nerve Tissue Proteins - genetics / Nerve Tissue Proteins - metabolism / Protein Binding / Protein Domains / Protein Folding / Protein interaction / Proteins / Proteostasis / Recruitment / Science / Science (multidisciplinary) / Structure-function relationships / Substrate Specificity / Substrates