6H3C

Cryo-EM structure of the BRISC complex bound to SHMT2

Summary for 6H3C

• Entry DOI: 10.2210/pdb6h3c/pdb
• Related: 6GVW
• EMDB information: 0132
• Descriptor: BRISC complex subunit Abraxas 2, Lys-63-specific deubiquitinase BRCC36, BRISC and BRCA1-A complex member 2, ... (7 entities in total)
• Functional Keywords: deubiquitinase complex, dub, lysine-63 linkage specific, brcc36-containing, brca1a binding, signaling protein
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 10
• Total formula weight: 458077.08

Authors

Bunker, R.D.,Rabl, J.,Thoma, N.H. (deposition date: 2018-07-18, release date: 2019-07-10, Last modification date: 2024-05-15)

Primary citation

Rabl, J.,Bunker, R.D.,Schenk, A.D.,Cavadini, S.,Gill, M.E.,Abdulrahman, W.,Andres-Pons, A.,Luijsterburg, M.S.,Ibrahim, A.F.M.,Branigan, E.,Aguirre, J.D.,Marceau, A.H.,Guerillon, C.,Bouwmeester, T.,Hassiepen, U.,Peters, A.H.F.M.,Renatus, M.,Gelman, L.,Rubin, S.M.,Mailand, N.,van Attikum, H.,Hay, R.T.,Thoma, N.H.
Structural Basis of BRCC36 Function in DNA Repair and Immune Regulation.
Mol.Cell, 75:483-497.e9, 2019

PubMed Abstract: In mammals, ∼100 deubiquitinases act on ∼20,000 intracellular ubiquitination sites. Deubiquitinases are commonly regarded as constitutively active, with limited regulatory and targeting capacity. The BRCA1-A and BRISC complexes serve in DNA double-strand break repair and immune signaling and contain the lysine-63 linkage-specific BRCC36 subunit that is functionalized by scaffold subunits ABRAXAS and ABRO1, respectively. The molecular basis underlying BRCA1-A and BRISC function is currently unknown. Here we show that in the BRCA1-A complex structure, ABRAXAS integrates the DNA repair protein RAP80 and provides a high-affinity binding site that sequesters the tumor suppressor BRCA1 away from the break site. In the BRISC structure, ABRO1 binds SHMT2α, a metabolic enzyme enabling cancer growth in hypoxic environments, which we find prevents BRCC36 from binding and cleaving ubiquitin chains. Our work explains modularity in the BRCC36 DUB family, with different adaptor subunits conferring diversified targeting and regulatory functions.

PubMed: 31253574
DOI: 10.1016/j.molcel.2019.06.002

Experimental method

ELECTRON MICROSCOPY (3.9 Å)