9SQV

Cryo-EM structure of the ARISCdC(E33A):K63-Ub4 complex (Composite map)

Summary for 9SQV

• Entry DOI: 10.2210/pdb9sqv/pdb
• EMDB information: 55118
• Descriptor: Ubiquitin, BRCA1-A complex subunit Abraxas 1, Lys-63-specific deubiquitinase BRCC36, ... (5 entities in total)
• Functional Keywords: deubiquitylating enzymes, jamm/mpn family, ubiquitin chains, dna damage repair, hydrolase
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 8
• Total formula weight: 244878.35

Authors

Foglizzo, M.,Degtjarik, O.,Zeqiraj, E. (deposition date: 2025-09-23, release date: 2026-08-05, Last modification date: 2026-08-26)

Primary citation

Foglizzo, M.,Datta, A.,Degtjarik, O.,Perera, H.,Liburd, J.,Sykora, U.M.,Ganji, S.R.,Wildsmith, G.,Chandler, F.,Campbell, L.J.,Calabrese, A.N.,Greenberg, R.A.,Zeqiraj, E.
Mechanism of K63-linked polyubiquitin recognition and cleavage by the BRCA1-A complex.
Nat Commun, 17:-, 2026

PubMed Abstract: Deubiquitylases modulate cellular processes by removing monoubiquitin or cleaving polyubiquitin chains. The ARISC-RAP80 complex partners with BRCA1-BARD1 to form the BRCA1-A supercomplex, which recognises K63-linked ubiquitin chains at DNA damage sites. ARISC-RAP80 contains multiple ubiquitin-binding sites, yet how these influence recognition and cleavage of K63-polyubiquitylated substrates remains unknown. We discover that a composite three-subunit interface allows ARISC-RAP80 to position K63-linked polyubiquitin chains in its catalytic site. Substrate recognition is further supported by RAP80 and non-catalytic ubiquitin-binding sites that impose a compact conformation on K63-polyubiquitylated substrates. This mechanism exploits the inherent flexibility of long ubiquitin chains and differs considerably from other deubiquitylases. Structure-guided mutageneses validate ubiquitin chain interactions, and cell-based assays demonstrate a functional role of the observed interfaces in chromatin recruitment. Our findings define mechanisms of polyubiquitin chain decoding and cleavage by ARISC-RAP80, linking ubiquitin reading and erasing functions to BRCA1-A mediated DNA damage responses.

PubMed: 42581301
DOI: 10.1038/s41467-026-75795-y

Experimental method

ELECTRON MICROSCOPY (3.21 Å)