20220319 Hsu STD Epub

Impacts of cancer-associated mutations on the structure-activity relationship of BAP1

Impacts of cancer-associated mutations on the structure-activity relationship of BAP1

Journal of Molecular Biology. 2022 May 15; 434(9):167553. Epub 2022 Mar 19.
doi: 10.1016/j.jmb.2022.167553

閱讀文章

Puri S, Chiu YH, Draczkowski P, Ko KT, Yang TJ, Wang YS, Uchiyama S, Hsu STD*

摘要

BRAC1 associated protein-1 (BAP1) is a major tumor suppressor involved in many cancers. The deubiquitinase (DUB) activity of BAP1 is essential for its nuclear localization, histone remodeling and proteostasis associated with mitochondrial calcium flux. Loss of the DUB activity due to catalytic mutations within the ubiquitin C-terminal hydrolase (UCH) domain of BAP1 (BAP1-UCH) directly contributes to oncogenesis. Nevertheless, it is non-trivial to rationalize how the other high-frequency but non-catalytic mutations within the BAP1-UCH lead to malignancies. Here we used multiplex spectroscopic, thermodynamic and biophysical analyses to investigate the impacts of eleven high-occurrence mutations within BAP1-UCH on the structure, folding and function. Several mutations significantly destabilize BAP1-UCH and increase its aggregation propensity. Hydrogen-deuterium exchange mass spectrometry data revealed allosteric destabilizations caused by mutations distant from the catalytic site. Our findings gave a comprehensive and multiscale account of the molecular basis of how these non-catalytic mutations within BAP1-UCH may be implicated in oncogenesis.