6M14

Crystal Structure of the BARD1 BRCT Mutant

Summary for 6M14

• Entry DOI: 10.2210/pdb6m14/pdb
• Descriptor: BRCA1-associated RING domain protein 1, SULFATE ION (3 entities in total)
• Functional Keywords: brct, disease mutation, ola1, antitumor protein, transferase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 48329.94

Authors

Chen, T.,Huang, W.T. (deposition date: 2020-02-24, release date: 2021-02-24, Last modification date: 2023-11-29)

Primary citation

Chen, T.,Yeh, H.W.,Chen, P.P.,Huang, W.T.,Wu, C.Y.,Liao, T.C.,Lin, S.L.,Chen, Y.Y.,Lin, K.T.,Hsu, S.D.,Cheng, H.C.
BARD1 is an ATPase activating protein for OLA1.
Biochim Biophys Acta Gen Subj, 1866:130099-130099, 2022

PubMed Abstract: 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 (k). 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.

PubMed: 35134491
DOI: 10.1016/j.bbagen.2022.130099

Experimental method

X-RAY DIFFRACTION (1.88001831059 Å)