20220205 Hsu STD Epub

BARD1 is an ATPase activating protein for OLA1

BARD1 is an ATPase activating protein for OLA1

Biochim Biophys Acta Gen Subj. 2022 May; 1866(5):130099. Epub 2022 Feb 5.
doi: 10.1016/j.bbagen.2022.130099

閱讀文章

Chen T, Yeh HW, Chen PP, Huang WT, Wu CY, Liao TC, Lin SL, Chen YY, Lin KT, Hsu STD, Cheng HC*

摘要

OLA1 is a P-loop ATPase, implicated in centrosome duplication through the interactions with tumor suppressors BRCA1 and BARD1. Disruption of the interaction of OLA1 with BARD1 results in centrosome amplification. However, the molecular interplay and mechanism of the OLA1-BARD1 complex remain elusive. Here, we use a battery of biophysical, biochemical, and structural analyses to elucidate the molecular basis of the OLA1-BARD1 interaction. Our structural and enzyme kinetics analyses show this nucleotide-dependent interaction enhances the ATPase activity of OLA1 by increasing the turnover number (kcat). Unlike canonical GTPase activating proteins that act directly on the catalytic G domain, the BARD1 BRCT domain binds to the OLA1 TGS domain via a highly conserved BUDR motif. A cancer related mutation V695L on BARD1 is known to associate with centrosome abnormality. The V695L mutation reduces the BARD1 BRCT-mediated activation of OLA1. Crystallographic snapshot of the BRCT V695L mutant at 1.88 Å reveals this mutation perturbs the OLA1 binding site, resulting in reduced interaction. Altogether, our findings suggest the BARD1 BRCT domain serves as an ATPase activating protein to control OLA1 allosterically.