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- PDB-6gvw: Crystal structure of the BRCA1-A complex -

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Basic information

Entry
Database: PDB / ID: 6gvw
TitleCrystal structure of the BRCA1-A complex
Components
  • (BRCA1-A complex subunit ...) x 2
  • (BRISC and BRCA1-A complex member ...) x 2
  • Lys-63-specific deubiquitinase BRCC36
KeywordsSIGNALING PROTEIN / Deubiquitinase complex / DUB / Lysine-63 linkage specific / BRCC36-containing / BRCA1A binding
Function / homology
Function and homology information


mitotic G2 DNA damage checkpoint signaling => GO:0007095 / : / : / BRISC complex / G2/M DNA damage checkpoint / Processing of DNA double-strand break ends / Nonhomologous End-Joining (NHEJ) / Metalloprotease DUBs / BRCA1-A complex / Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks ...mitotic G2 DNA damage checkpoint signaling => GO:0007095 / : / : / BRISC complex / G2/M DNA damage checkpoint / Processing of DNA double-strand break ends / Nonhomologous End-Joining (NHEJ) / Metalloprotease DUBs / BRCA1-A complex / Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks / ubiquitin-modified histone reader activity / attachment of spindle microtubules to kinetochore / nuclear ubiquitin ligase complex / Hydrolases; Acting on peptide bonds (peptidases); Omega peptidases / mitotic G2/M transition checkpoint / tumor necrosis factor receptor binding / protein K63-linked deubiquitination / DNA repair-dependent chromatin remodeling / K63-linked polyubiquitin modification-dependent protein binding / hematopoietic stem cell proliferation / response to ionizing radiation / mitotic G2 DNA damage checkpoint signaling / polyubiquitin modification-dependent protein binding / response to X-ray / mitotic spindle assembly / regulation of DNA repair / enzyme regulator activity / ubiquitin ligase complex / nuclear retinoid X receptor binding / positive regulation of DNA repair / spindle pole / metallopeptidase activity / double-strand break repair / site of double-strand break / chromatin organization / histone binding / microtubule binding / cysteine-type deubiquitinase activity / nuclear body / cell cycle / cell division / negative regulation of DNA-templated transcription / apoptotic process / DNA damage response / negative regulation of apoptotic process / DNA binding / nucleoplasm / metal ion binding / nucleus / cytosol / cytoplasm
Similarity search - Function
BRISC and BRCA1-A complex member 1 / BRCA1-A complex subunit BRE / FAM175 family, BRCA1-A complex, Abraxas 1 subunit / Brain and reproductive organ-expressed protein (BRE) / BRCA1-A complex subunit RAP80 / RAP80, N-terminal / RAP80 N-terminal ubiquitin interaction motif / Brcc36 isopeptidase / BRCC36, C-terminal helical domain / BRCC36 C-terminal helical domain ...BRISC and BRCA1-A complex member 1 / BRCA1-A complex subunit BRE / FAM175 family, BRCA1-A complex, Abraxas 1 subunit / Brain and reproductive organ-expressed protein (BRE) / BRCA1-A complex subunit RAP80 / RAP80, N-terminal / RAP80 N-terminal ubiquitin interaction motif / Brcc36 isopeptidase / BRCC36, C-terminal helical domain / BRCC36 C-terminal helical domain / FAM175 family / Ubiquitin-interacting motif. / Rad18, zinc finger UBZ4-type / Zinc finger UBZ4-type profile. / Ubiquitin interacting motif / Ubiquitin-interacting motif (UIM) domain profile. / JAB1/Mov34/MPN/PAD-1 ubiquitin protease / JAB/MPN domain / JAB1/MPN/MOV34 metalloenzyme domain / MPN domain / MPN domain profile. / von Willebrand factor A-like domain superfamily
Similarity search - Domain/homology
Lys-63-specific deubiquitinase BRCC36 / BRISC and BRCA1-A complex member 1 / BRCA1-A complex subunit RAP80 / BRCA1-A complex subunit Abraxas 1 / BRISC and BRCA1-A complex member 2
Similarity search - Component
Biological speciesMus musculus (house mouse)
MethodX-RAY DIFFRACTION / SYNCHROTRON / SAD / Resolution: 3.75 Å
AuthorsBunker, R.D. / Rabl, J. / Thoma, N.H.
CitationJournal: 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
DepositionJun 21, 2018Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jul 10, 2019Provider: repository / Type: Initial release
Revision 1.1Aug 21, 2019Group: Data collection / Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: BRCA1-A complex subunit Abraxas 1
B: Lys-63-specific deubiquitinase BRCC36
C: BRISC and BRCA1-A complex member 2
D: BRISC and BRCA1-A complex member 1
E: BRCA1-A complex subunit RAP80
F: BRCA1-A complex subunit Abraxas 1
G: Lys-63-specific deubiquitinase BRCC36
H: BRISC and BRCA1-A complex member 2
I: BRISC and BRCA1-A complex member 1
J: BRCA1-A complex subunit RAP80
hetero molecules


Theoretical massNumber of molelcules
Total (without water)337,21412
Polymers337,08310
Non-polymers1312
Water362
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: microscopy
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area52140 Å2
ΔGint-430 kcal/mol
Surface area112080 Å2
MethodPISA
Unit cell
Length a, b, c (Å)97.096, 122.645, 431.325
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11A
21F
12B
22G
13C
23H
14D
24I
15E
25J

NCS domain segments:
Dom-IDComponent-IDEns-IDRefine codeAuth asym-IDAuth seq-ID
1010A3 - 323
2010F3 - 323
1020B8 - 291
2020G8 - 291
1030C1 - 383
2030H1 - 383
1040D84 - 320
2040I84 - 320
1050E272 - 330
2050J272 - 330

NCS ensembles :
IDDetails
5E, J
1A, F
2B, G
3C, H
4D, I

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Components

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BRCA1-A complex subunit ... , 2 types, 4 molecules AFEJ

#1: Protein BRCA1-A complex subunit Abraxas 1 / Coiled-coil domain-containing protein 98 / Protein FAM175A


Mass: 46431.422 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Gene: Abraxas1, Abra1, Ccdc98, Fam175a / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: Q8BPZ8
#5: Protein BRCA1-A complex subunit RAP80 / Receptor-associated protein 80 / Ubiquitin interaction motif-containing protein 1


Mass: 7327.536 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Gene: Uimc1, Rap80, Rip110, Rxrip110 / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: Q5U5Q9

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Protein , 1 types, 2 molecules BG

#2: Protein Lys-63-specific deubiquitinase BRCC36 / BRCA1-A complex subunit BRCC36 / BRCA1/BRCA2-containing complex subunit 3 / BRCA1/BRCA2-containing ...BRCA1-A complex subunit BRCC36 / BRCA1/BRCA2-containing complex subunit 3 / BRCA1/BRCA2-containing complex subunit 36 / BRISC complex subunit BRCC36


Mass: 33711.422 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Gene: Brcc3, Brcc36, C6.1a / Production host: Trichoplusia ni (cabbage looper)
References: UniProt: P46737, Hydrolases; Acting on peptide bonds (peptidases); Omega peptidases

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BRISC and BRCA1-A complex member ... , 2 types, 4 molecules CHDI

#3: Protein BRISC and BRCA1-A complex member 2 / BRCA1-A complex subunit BRE / BRCA1/BRCA2-containing complex subunit 45 / Brain and reproductive ...BRCA1-A complex subunit BRE / BRCA1/BRCA2-containing complex subunit 45 / Brain and reproductive organ-expressed protein


Mass: 43915.836 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Gene: Babam2, Bre / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: Q8K3W0
#4: Protein BRISC and BRCA1-A complex member 1 / Mediator of RAP80 interactions and targeting subunit of 40 kDa / New component of the BRCA1-A complex


Mass: 37155.367 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Gene: Babam1, Merit40, Nba1 / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: Q3UI43

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Non-polymers , 2 types, 4 molecules

#6: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Zn
#7: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestN

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

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Sample preparation

CrystalDensity Matthews: 3.81 Å3/Da / Density % sol: 67.71 %
Crystal growTemperature: 292 K / Method: vapor diffusion, hanging drop
Details: 100 mM MES-KOH pH 5.6, 200 mM MgCl2, 8% (w/v) PEG6000

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06SA / Wavelength: 1 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Sep 10, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 3.75→30 Å / Num. obs: 53796 / % possible obs: 100 % / Observed criterion σ(I): -3 / Redundancy: 51.9 % / Biso Wilson estimate: 163 Å2 / CC1/2: 0.952 / Rmerge(I) obs: 0.173 / Rrim(I) all: 0.175 / Χ2: 1.19 / Net I/σ(I): 11.6
Reflection shellResolution: 3.75→3.814 Å / Redundancy: 52.8 % / Rmerge(I) obs: 15.709 / Mean I/σ(I) obs: 0.4 / Num. unique obs: 2661 / CC1/2: 0.476 / Rrim(I) all: 15.86 / Χ2: 1.45 / % possible all: 100

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Processing

Software
NameVersionClassification
REFMAC5.8.0238refinement
DIALSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: SAD / Resolution: 3.75→29.99 Å / Cor.coef. Fo:Fc: 0.956 / Cor.coef. Fo:Fc free: 0.942 / SU B: 131.227 / SU ML: 0.765 / Cross valid method: THROUGHOUT / ESU R Free: 0.728 / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.2591 2214 5 %RANDOM
Rwork0.22732 ---
obs0.22896 42193 82.34 %-
Solvent computationIon probe radii: 0.9 Å / Shrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å
Displacement parametersBiso mean: 209.67 Å2
Baniso -1Baniso -2Baniso -3
1-8.36 Å2-0 Å20 Å2
2---1.5 Å2-0 Å2
3----6.87 Å2
Refinement stepCycle: LAST / Resolution: 3.75→29.99 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms20134 0 2 2 20138
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0060.01320616
X-RAY DIFFRACTIONr_bond_other_d0.0010.01718854
X-RAY DIFFRACTIONr_angle_refined_deg1.1471.64227941
X-RAY DIFFRACTIONr_angle_other_deg1.3611.56743936
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.38852503
X-RAY DIFFRACTIONr_dihedral_angle_2_deg30.11422.951078
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.334153586
X-RAY DIFFRACTIONr_dihedral_angle_4_deg12.33215108
X-RAY DIFFRACTIONr_chiral_restr0.0540.22648
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.0222805
X-RAY DIFFRACTIONr_gen_planes_other0.0010.024207
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it5.33314.05910054
X-RAY DIFFRACTIONr_mcbond_other5.33314.05910053
X-RAY DIFFRACTIONr_mcangle_it8.95321.08712543
X-RAY DIFFRACTIONr_mcangle_other8.95321.08712544
X-RAY DIFFRACTIONr_scbond_it4.86314.41210562
X-RAY DIFFRACTIONr_scbond_other4.86314.41210563
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other8.37921.45515399
X-RAY DIFFRACTIONr_long_range_B_refined15.97278149
X-RAY DIFFRACTIONr_long_range_B_other15.97278150
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
Refine LS restraints NCS

Refine-ID: X-RAY DIFFRACTION / Type: interatomic distance / Weight position: 0.05

Ens-IDDom-IDAuth asym-IDNumberRms dev position (Å)
11A82760.18
12F82760.18
21B76930.14
22G76930.14
31C109000.14
32H109000.14
41D64180.18
42I64180.18
51E15630.12
52J15630.12
LS refinement shellResolution: 3.75→3.846 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.367 78 -
Rwork0.382 1269 -
obs--34.83 %
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
11.8824-1.1986-1.21632.13370.74242.016-0.268-0.4303-0.17930.36240.03890.01490.46950.33470.22920.16080.0205-0.10240.91930.49311.0512.117-4.9587.702
22.363-0.7602-0.85241.6932-0.07832.9677-0.08980.1881-0.5469-0.2167-0.20190.39080.644-0.30260.29180.3318-0.1557-0.01130.73140.31211.36673.864-18.4-10.076
32.6116-2.3683-0.59553.12560.24871.1731-0.0703-0.14620.08190.3205-0.0378-0.1332-0.25660.25990.1080.1296-0.1878-0.13560.92990.31950.708-9.08234.40619.504
45.8304-0.4604-0.14793.3230.13193.03790.1569-0.2127-0.75270.2128-0.1040.81370.4904-0.8965-0.0530.1093-0.16260.05130.99320.2721.2751-47.83928.82221.231
55.7722-1.0533-2.62510.44181.16053.32670.0872-0.4271-0.46320.0805-0.04730.0186-0.0846-0.1316-0.03990.45690.0885-0.0070.87470.45760.796-18.67935.10728.409
60.73870.0861-0.49551.1857-0.92164.0153-0.1229-0.0371-0.2236-0.36720.2550.25740.7495-0.1752-0.13220.79950.10430.10880.61370.15151.152837.865-15.362-62.547
72.2065-0.4586-0.57513.13670.31383.912-0.0608-0.39690.0792-0.1150.3897-0.4754-0.2130.5293-0.32890.69910.27280.16850.76120.13910.83949.414-9.41-41.55
80.11560.3798-0.40182.287-1.30722.8545-0.1920.06590.124-0.20030.48620.5594-0.0886-0.7542-0.29421.23540.14140.22360.75280.24691.05230.43114.672-96.095
92.05411.57330.24475.7077-1.22923.5332-0.1633-0.3407-0.07280.0488-0.0192-1.2508-0.36841.22180.18261.3993-0.06130.20.89760.03771.144362.31336.797-103.191
101.72561.02340.541.7557-0.69453.7384-0.01170.1405-0.0786-0.3546-0.0030.0255-0.0485-0.54310.01471.42940.02170.13860.37710.07770.872739.48716.818-105.226
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A3 - 324
2X-RAY DIFFRACTION2B8 - 1000
3X-RAY DIFFRACTION3C1 - 383
4X-RAY DIFFRACTION4D83 - 321
5X-RAY DIFFRACTION5E272 - 330
6X-RAY DIFFRACTION6F1 - 330
7X-RAY DIFFRACTION7G8 - 1000
8X-RAY DIFFRACTION8H1 - 383
9X-RAY DIFFRACTION9I84 - 321
10X-RAY DIFFRACTION10J272 - 330

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