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- PDB-6r8f: Cryo-EM structure of the Human BRISC-SHMT2 complex -

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Basic information

Entry
Database: PDB / ID: 6r8f
TitleCryo-EM structure of the Human BRISC-SHMT2 complex
Components
  • BRISC and BRCA1-A complex member 2,BRCC45 (BRE, BRISC and BRCA1-A complex member 2)
  • BRISC complex subunit Abraxas 2
  • Lys-63-specific deubiquitinase BRCC36
  • Serine hydroxymethyltransferase, mitochondrial
KeywordsSIGNALING PROTEIN / Complex / Deubiquitylation / Ubiquitin / Immune signalling
Function / homology
Function and homology information


peroxisome targeting sequence binding / BRISC complex / formate biosynthetic process / L-allo-threonine aldolase activity / BRCA1-A complex / regulation of mitochondrial translation / glycine metabolic process / attachment of spindle microtubules to kinetochore / L-serine metabolic process / regulation of oxidative phosphorylation ...peroxisome targeting sequence binding / BRISC complex / formate biosynthetic process / L-allo-threonine aldolase activity / BRCA1-A complex / regulation of mitochondrial translation / glycine metabolic process / attachment of spindle microtubules to kinetochore / L-serine metabolic process / regulation of oxidative phosphorylation / L-serine biosynthetic process / nuclear ubiquitin ligase complex / glycine hydroxymethyltransferase / glycine hydroxymethyltransferase activity / glycine biosynthetic process from serine / Metabolism of folate and pterines / Hydrolases; Acting on peptide bonds (peptidases); Omega peptidases / tetrahydrofolate metabolic process / regulation of DNA damage checkpoint / response to type I interferon / mitotic G2/M transition checkpoint / tumor necrosis factor receptor binding / metal-dependent deubiquitinase activity / protein K63-linked deubiquitination / tetrahydrofolate interconversion / regulation of aerobic respiration / K63-linked deubiquitinase activity / amino acid binding / response to ionizing radiation / DNA repair-dependent chromatin remodeling / positive regulation of NLRP3 inflammasome complex assembly / mitotic G2 DNA damage checkpoint signaling / mitochondrial nucleoid / RHOG GTPase cycle / polyubiquitin modification-dependent protein binding / protein deubiquitination / mitotic spindle assembly / ubiquitin ligase complex / response to X-ray / regulation of DNA repair / enzyme regulator activity / one-carbon metabolic process / Mitochondrial protein degradation / positive regulation of DNA repair / response to ischemia / cellular response to ionizing radiation / chromosome segregation / protein tetramerization / Nonhomologous End-Joining (NHEJ) / G2/M DNA damage checkpoint / Metalloprotease DUBs / metallopeptidase activity / spindle pole / pyridoxal phosphate binding / double-strand break repair / mitotic cell cycle / Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks / microtubule cytoskeleton / Processing of DNA double-strand break ends / chromatin organization / protein homotetramerization / microtubule binding / microtubule / cysteine-type deubiquitinase activity / mitochondrial inner membrane / ciliary basal body / mitochondrial matrix / cell division / positive regulation of cell population proliferation / apoptotic process / DNA damage response / chromatin binding / negative regulation of apoptotic process / signal transduction / mitochondrion / proteolysis / extracellular exosome / nucleoplasm / metal ion binding / identical protein binding / nucleus / cytoplasm / cytosol
Similarity search - Function
FAM175 family, BRISC complex, Abro1 subunit / BRCA1-A complex subunit BRE / Brain and reproductive organ-expressed protein (BRE) / Brcc36 isopeptidase / BRCC36, C-terminal helical domain / BRCC36 C-terminal helical domain / FAM175 family / BRCA1-A complex subunit Abraxas 1 MPN domain / Serine hydroxymethyltransferase, pyridoxal phosphate binding site / Serine hydroxymethyltransferase pyridoxal-phosphate attachment site. ...FAM175 family, BRISC complex, Abro1 subunit / BRCA1-A complex subunit BRE / Brain and reproductive organ-expressed protein (BRE) / Brcc36 isopeptidase / BRCC36, C-terminal helical domain / BRCC36 C-terminal helical domain / FAM175 family / BRCA1-A complex subunit Abraxas 1 MPN domain / Serine hydroxymethyltransferase, pyridoxal phosphate binding site / Serine hydroxymethyltransferase pyridoxal-phosphate attachment site. / : / Serine hydroxymethyltransferase / Serine hydroxymethyltransferase-like domain / Serine hydroxymethyltransferase / : / JAB1/Mov34/MPN/PAD-1 ubiquitin protease / JAB/MPN domain / JAB1/MPN/MOV34 metalloenzyme domain / MPN domain / MPN domain profile. / Pyridoxal phosphate-dependent transferase, small domain / Pyridoxal phosphate-dependent transferase, major domain / Pyridoxal phosphate-dependent transferase
Similarity search - Domain/homology
Serine hydroxymethyltransferase, mitochondrial / Lys-63-specific deubiquitinase BRCC36 / BRISC complex subunit Abraxas 2 / BRISC and BRCA1-A complex member 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.8 Å
AuthorsWalden, M. / Hesketh, E. / Tian, L. / Ranson, N.A. / Greenberg, R.A. / Zeqiraj, E.
Funding support United Kingdom, 1items
OrganizationGrant numberCountry
Wellcome Trust200523/Z/16/Z United Kingdom
CitationJournal: Nature / Year: 2019
Title: Metabolic control of BRISC-SHMT2 assembly regulates immune signalling.
Authors: Miriam Walden / Lei Tian / Rebecca L Ross / Upasana M Sykora / Dominic P Byrne / Emma L Hesketh / Safi K Masandi / Joel Cassel / Rachel George / James R Ault / Farid El Oualid / Krzysztof ...Authors: Miriam Walden / Lei Tian / Rebecca L Ross / Upasana M Sykora / Dominic P Byrne / Emma L Hesketh / Safi K Masandi / Joel Cassel / Rachel George / James R Ault / Farid El Oualid / Krzysztof Pawłowski / Joseph M Salvino / Patrick A Eyers / Neil A Ranson / Francesco Del Galdo / Roger A Greenberg / Elton Zeqiraj /
Abstract: Serine hydroxymethyltransferase 2 (SHMT2) regulates one-carbon transfer reactions that are essential for amino acid and nucleotide metabolism, and uses pyridoxal-5'-phosphate (PLP) as a cofactor. ...Serine hydroxymethyltransferase 2 (SHMT2) regulates one-carbon transfer reactions that are essential for amino acid and nucleotide metabolism, and uses pyridoxal-5'-phosphate (PLP) as a cofactor. Apo SHMT2 exists as a dimer with unknown functions, whereas PLP binding stabilizes the active tetrameric state. SHMT2 also promotes inflammatory cytokine signalling by interacting with the deubiquitylating BRCC36 isopeptidase complex (BRISC), although it is unclear whether this function relates to metabolism. Here we present the cryo-electron microscopy structure of the human BRISC-SHMT2 complex at a resolution of 3.8 Å. BRISC is a U-shaped dimer of four subunits, and SHMT2 sterically blocks the BRCC36 active site and inhibits deubiquitylase activity. Only the inactive SHMT2 dimer-and not the active PLP-bound tetramer-binds and inhibits BRISC. Mutations in BRISC that disrupt SHMT2 binding impair type I interferon signalling in response to inflammatory stimuli. Intracellular levels of PLP regulate the interaction between BRISC and SHMT2, as well as inflammatory cytokine responses. These data reveal a mechanism in which metabolites regulate deubiquitylase activity and inflammatory signalling.
History
DepositionApr 1, 2019Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jun 5, 2019Provider: repository / Type: Initial release
Revision 1.1Jun 12, 2019Group: Data collection / Database references
Category: citation / database_PDB_rev ...citation / database_PDB_rev / database_PDB_rev_record / em_admin / pdbx_database_proc / pdbx_seq_map_depositor_info
Item: _citation.pdbx_database_id_PubMed / _citation.title ..._citation.pdbx_database_id_PubMed / _citation.title / _em_admin.last_update / _pdbx_seq_map_depositor_info.one_letter_code_mod
Revision 1.2Jun 26, 2019Group: Data collection / Database references
Category: citation / em_admin ...citation / em_admin / pdbx_database_proc / pdbx_seq_map_depositor_info
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _em_admin.last_update / _pdbx_seq_map_depositor_info.one_letter_code_mod
Revision 1.3Dec 18, 2019Group: Data collection / Other / Category: atom_sites / em_image_scans
Item: _atom_sites.fract_transf_matrix[1][1] / _atom_sites.fract_transf_matrix[2][2] / _atom_sites.fract_transf_matrix[3][3]
Revision 1.4May 22, 2024Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / em_3d_fitting_list / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _em_3d_fitting_list.accession_code / _em_3d_fitting_list.initial_refinement_model_id / _em_3d_fitting_list.source_name / _em_3d_fitting_list.type

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Structure visualization

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Assembly

Deposited unit
A: Lys-63-specific deubiquitinase BRCC36
B: BRISC complex subunit Abraxas 2
K: Serine hydroxymethyltransferase, mitochondrial
C: Lys-63-specific deubiquitinase BRCC36
D: BRISC complex subunit Abraxas 2
L: Serine hydroxymethyltransferase, mitochondrial
E: BRISC and BRCA1-A complex member 2,BRCC45 (BRE, BRISC and BRCA1-A complex member 2)
G: BRISC and BRCA1-A complex member 2,BRCC45 (BRE, BRISC and BRCA1-A complex member 2)
hetero molecules


Theoretical massNumber of molelcules
Total (without water)290,68810
Polymers290,5578
Non-polymers1312
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area34500 Å2
ΔGint-276 kcal/mol
Surface area94480 Å2
MethodPISA

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Components

#1: 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: 36119.918 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: BRCC3, BRCC36, C6.1A, CXorf53 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P46736, Hydrolases; Acting on peptide bonds (peptidases); Omega peptidases
#2: Protein BRISC complex subunit Abraxas 2 / Abraxas brother protein 1 / Protein FAM175B


Mass: 31033.945 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ABRAXAS2, ABRO1, FAM175B, KIAA0157 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q15018
#3: Protein Serine hydroxymethyltransferase, mitochondrial / SHMT / Glycine hydroxymethyltransferase / Serine methylase


Mass: 56097.902 Da / Num. of mol.: 2 / Mutation: A285T
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SHMT2 / Production host: Escherichia coli (E. coli)
References: UniProt: P34897, glycine hydroxymethyltransferase
#4: Protein BRISC and BRCA1-A complex member 2,BRCC45 (BRE, 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: 22026.717 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: BABAM2, BRCC45, BRE, BABAM2 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q9NXR7
#5: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Zn

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

Component
IDNameTypeEntity IDParent-IDSourceDetails
1BRISC-SHMT2COMPLEX#1-#40MULTIPLE SOURCES
2MERIT40 (BRISC and BRCA1-A complex member 1)COMPLEX#1-#2, #41RECOMBINANTMERIT40 also expressed along with other macromolecules, but no model is built into the low resolution density.
3Serine hydroxymethyltransferase, mitochondrialCOMPLEX#31RECOMBINANT
Molecular weightValue: 388.47 kDa/nm / Experimental value: YES
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
22Homo sapiens (human)9606
33Homo sapiens (human)9606
Source (recombinant)
IDEntity assembly-IDOrganismNcbi tax-ID
22Spodoptera frugiperda (fall armyworm)7108
33Escherichia coli (E. coli)562
Buffer solutionpH: 7.5
Buffer component
IDConc.NameFormulaBuffer-ID
125 mMHEPES1
2150 mMNaCl1
31 mMTCEP1
SpecimenConc.: 0.051 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Details: Specimen contained BRCC36, ABRAXAS2, BRCC45, MERIT40 and SHMT2 macromolecules
Specimen supportGrid material: COPPER / Grid type: Quantifoil R1.2/1.3
VitrificationCryogen name: ETHANE / Humidity: 95 % / Chamber temperature: 277 K

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal magnification: 75000 X / Nominal defocus max: -1600 nm / Nominal defocus min: -3100 nm / Cs: 2.7 mm / C2 aperture diameter: 70 µm / Alignment procedure: COMA FREE
Specimen holderCryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingAverage exposure time: 2 sec. / Electron dose: 1.2 e/Å2 / Detector mode: INTEGRATING / Film or detector model: FEI FALCON III (4k x 4k) / Num. of grids imaged: 3 / Num. of real images: 7494

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Processing

SoftwareName: PHENIX / Version: 1.11.1_2575: / Classification: refinement
EM software
IDNameCategory
1RELIONparticle selection
2EPUimage acquisition
4RELIONCTF correction
7UCSF Chimeramodel fitting
9PHENIXmodel refinement
10RELIONinitial Euler assignment
11RELIONfinal Euler assignment
12RELIONclassification
13RELION3D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
SymmetryPoint symmetry: C1 (asymmetric)
3D reconstructionResolution: 3.8 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 403499 / Symmetry type: POINT
Atomic model buildingProtocol: RIGID BODY FIT
Atomic model building
IDPDB-ID 3D fitting-IDAccession codeInitial refinement model-IDSource nameType
15CW3

5cw3

15CW31PDBexperimental model
26DK3

6dk3

16DK32PDBexperimental model

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