Journal: Mol Cell / Year: 2019 Title: Structural Basis of BRCC36 Function in DNA Repair and Immune Regulation. Authors: Julius Rabl / Richard D Bunker / Andreas D Schenk / Simone Cavadini / Mark E Gill / Wassim Abdulrahman / Amparo Andrés-Pons / Martijn S Luijsterburg / Adel F M Ibrahim / Emma Branigan / ...Authors: Julius Rabl / Richard D Bunker / Andreas D Schenk / Simone Cavadini / Mark E Gill / Wassim Abdulrahman / Amparo Andrés-Pons / Martijn S Luijsterburg / Adel F M Ibrahim / Emma Branigan / Jacob D Aguirre / Aimee H Marceau / Claire Guérillon / Tewis Bouwmeester / Ulrich Hassiepen / Antoine H F M Peters / Martin Renatus / Laurent Gelman / Seth M Rubin / Niels Mailand / Haico van Attikum / Ronald T Hay / Nicolas H Thomä / 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. ...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.
History
Deposition
Jul 18, 2018
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Header (metadata) release
Jul 3, 2019
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Map release
Jul 10, 2019
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Update
May 15, 2024
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Current status
May 15, 2024
Processing site: PDBe / Status: Released
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Structure visualization
Movie
Surface view with section colored by density value
Cryogen name: ETHANE / Chamber humidity: 80 % / Chamber temperature: 277 K / Instrument: LEICA EM GP Details: A 4 ul sample was applied to the grid and a protocol consisting of 30 s pre-blot incubation, 2 s blotting and no post-blot incubation was utilized for vitrification..
Details
Sample was purified by gel filtration over a Superose 6 column.
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Electron microscopy
Microscope
FEI TITAN KRIOS
Specialist optics
Spherical aberration corrector: CEOS Cs-corrector / Energy filter - Name: GIF Quantum LS / Energy filter - Slit width: 20 eV
Image recording
Film or detector model: GATAN K2 SUMMIT (4k x 4k) / Detector mode: COUNTING / Digitization - Dimensions - Width: 3710 pixel / Digitization - Dimensions - Height: 3838 pixel / Digitization - Frames/image: 4-20 / Number real images: 1822 / Average exposure time: 7.0 sec. / Average electron dose: 45.0 e/Å2
Electron beam
Acceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
chain_id: A, source_name: PDB, initial_model_type: experimental model
Details
Initial fitting with done using COOT, Rosetta was used for amino acid sequence threading and flexible fitting. COOT and ISOLDE were used for local rebuilding. Phenix was used for atom displacement parameter (ADP / B-factor) refinement.
Refinement
Space: REAL / Protocol: FLEXIBLE FIT / Overall B value: 117 / Target criteria: Correlation coefficient and
Output model
PDB-6h3c: Cryo-EM structure of the BRISC complex bound to SHMT2
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