9SMS

BRCA1-A complex: Ubiquitin bound to BRE at the wrist site (focused 3D class)

Summary for 9SMS

• Entry DOI: 10.2210/pdb9sms/pdb
• EMDB information: 55041
• Descriptor: BRCA1-A complex subunit Abraxas 1, BRISC and BRCA1-A complex member 2, BRISC and BRCA1-A complex member 1, ... (5 entities in total)
• Functional Keywords: deubiquitinase; dna repair; metalloprotein; ubiquitin chains;, metal binding protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 5
• Total formula weight: 156856.61

Authors

Murachelli, A.G.,Sixma, T.K. (deposition date: 2025-09-09, release date: 2026-06-17, Last modification date: 2026-08-19)

Primary citation

Murachelli, A.G.,El Oualid, F.,Sixma, T.K.
A ubiquitin chain-feeding mechanism for BRCA1-A.
Nat Commun, 17:-, 2026

PubMed Abstract: The BRCA1-A complex is a multi-subunit, metallo-deubiquitinating enzyme (metallo-DUB) involved in genome maintenance. BRCA1-A displays strict specificity for K63-linked ubiquitin, with a strong preference for long chains, but the mechanistic basis for this selectivity has remained unclear. To address this, we have developed an activity-based probe that is specific for metallo-DUBs and mimics di- or polyubiquitin chains of any linkage (di- and poly-ubiquitin). We have solved cryoEM structures of BRCA1-A bound to K63-linked probe chains of various length, capturing multiple conformational and catalytic states. The structures reveal how allosteric regulation of catalysis occurs within the complex and how BRCA1-A uses auxiliary ubiquitin-binding sites to engage substrate by avidity and to trigger processive cleavage. Crucially, avidity and processivity can only apply to long polyubiquitin chains, explaining BRCA1-A's substrate preference. Together, these results establish BRCA1-A as a chain-shortening DUB specialised for trimming extended K63-linked polyubiquitin chains.

PubMed: 42581048
DOI: 10.1038/s41467-026-75797-w

Experimental method

ELECTRON MICROSCOPY (3.3 Å)