Abstract
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.
Original language | English |
---|---|
Pages (from-to) | 1512-1526.e9 |
Journal | Molecular Cell |
Volume | 84 |
Issue number | 8 |
DOIs | |
Publication status | Published Online - 19 Mar 2024 |
Funding
The authors would like to thank C.S. Tran for cell culture and microscopy assistance, T. Scherf for NMR support, and the Clore Institute for High-Field Magnetic Resonance Imaging and Spectroscopy. We also thank V. Rotter, M. Oren, Z. Shakked, J. Tittelmeier, C. Nussbaum-Krammer, M.P. Latham, and D.F. Hansen for helpful discussions and advice; N. Nillegoda for contributions to funding acquisition; and Y. Mor-Scheerer for aiding with graphical illustrations. R.R. is supported by the European Research Council starting grant (ERC-2018-STG 802001), the Minerva Foundation, and a research grant from the Blythe Brenden-Mann New-Scientist Fund. R.R. and B.B are supported by the IMOS - DKFZ - Cooperation in Cancer Research. B.B. is supported by grant BU617/21-1 from the Deutsche Forschungsgemeinschaft. Publisher Copyright: © 2024 Elsevier Inc.
All Science Journal Classification (ASJC) codes
- Molecular Biology
- Cell Biology