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- EMDB-4760: Cryo-EM structure of the Human BRISC-SHMT2 complex, C2 reconstruction -

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Basic information

Entry
Database: EMDB / ID: EMD-4760
TitleCryo-EM structure of the Human BRISC-SHMT2 complex, C2 reconstruction
Map dataC2 reconstruction. Filtered by local resolution in RELION.
Sample
  • Complex: BRISC-SHMT2
    • Protein or peptide: BRCC36
    • Protein or peptide: ABRAXAS2
    • Protein or peptide: BRCC45 (BRE)
    • Protein or peptide: MERIT40 (BABAM1)
    • Protein or peptide: SHMT2Serine hydroxymethyltransferase
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 4.2 Å
AuthorsWalden M / Tian L / Hesketh E / Ranson NA / Greenberg RA / Zeqiraj E
Funding support United Kingdom, 1 items
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, 2019-
Header (metadata) releaseJun 5, 2019-
Map releaseJun 5, 2019-
UpdateNov 25, 2020-
Current statusNov 25, 2020Processing site: PDBe / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.05
  • Imaged by UCSF Chimera
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  • Surface view colored by radius
  • Surface level: 0.05
  • Imaged by UCSF Chimera
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_4760.png

Downloads & links

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Map

FileDownload / File: emd_4760.map.gz / Format: CCP4 / Size: 163.6 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationC2 reconstruction. Filtered by local resolution in RELION.
Voxel sizeX=Y=Z: 1.0651 Å
Density
Contour LevelBy AUTHOR: 0.05 / Movie #1: 0.05
Minimum - Maximum-0.18069613 - 0.41042942
Average (Standard dev.)-0.00010889793 (±0.008392092)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions350350350
Spacing350350350
CellA=B=C: 372.78497 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.06511.06511.0651
M x/y/z350350350
origin x/y/z0.0000.0000.000
length x/y/z372.785372.785372.785
α/β/γ90.00090.00090.000
start NX/NY/NZ000
NX/NY/NZ320320320
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS350350350
D min/max/mean-0.1810.410-0.000

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Supplemental data

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Half map: C2 refinement half map 1.

Fileemd_4760_half_map_1.map
AnnotationC2 refinement half map 1.
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: C2 refinement half map 2.

Fileemd_4760_half_map_2.map
AnnotationC2 refinement half map 2.
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : BRISC-SHMT2

EntireName: BRISC-SHMT2
Components
  • Complex: BRISC-SHMT2
    • Protein or peptide: BRCC36
    • Protein or peptide: ABRAXAS2
    • Protein or peptide: BRCC45 (BRE)
    • Protein or peptide: MERIT40 (BABAM1)
    • Protein or peptide: SHMT2Serine hydroxymethyltransferase

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Supramolecule #1: BRISC-SHMT2

SupramoleculeName: BRISC-SHMT2 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)
Molecular weightExperimental: 388.47 kDa/nm

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Macromolecule #1: BRCC36

MacromoleculeName: BRCC36 / type: protein_or_peptide / ID: 1 / Enantiomer: LEVO
EC number: Hydrolases; Acting on peptide bonds (peptidases); Omega peptidases
Source (natural)Organism: Homo sapiens (human)
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MAVQVVQAVQ AVHLESDAFL VCLNHALSTE KEEVMGLCIG ELNDDTRSDS KFAYTGTEMR TVAEKVDAVR IVHIHSVIIL RRSDKRKDRV EISPEQLSAA STEAERLAEL TGRPMRVVGW YHSHPHITVW PSHVDVRTQA MYQMMDQGFV GLIFSCFIED KNTKTGRVLY ...String:
MAVQVVQAVQ AVHLESDAFL VCLNHALSTE KEEVMGLCIG ELNDDTRSDS KFAYTGTEMR TVAEKVDAVR IVHIHSVIIL RRSDKRKDRV EISPEQLSAA STEAERLAEL TGRPMRVVGW YHSHPHITVW PSHVDVRTQA MYQMMDQGFV GLIFSCFIED KNTKTGRVLY TCFQSIQAQK SSESLHGPRD FWSSSQHISI EGQKEEERYE RIEIPIHIVP HVTIGKVCLE SAVELPKILC QEEQDAYRRI HSLTHLDSVT KIHNGSVFTK NLCSQMSAVS GPLLQWLEDR LEQNQQHLQE LQQEKEELMQ ELSSLE

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Macromolecule #2: ABRAXAS2

MacromoleculeName: ABRAXAS2 / type: protein_or_peptide / ID: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MAASISGYTF SAVCFHSANS NADHEGFLLG EVRQEETFSI SDSQISNTEF LQVIEIHNHQ PCSKLFSFYD YASKVNEESL DRILKDRRKK VIGWYRFRRN TQQQMSYREQ VLHKQLTRIL GVPDLVFLLF SFISTANNST HALEYVLFRP NRRYNQRISL AIPNLGNTSQ ...String:
MAASISGYTF SAVCFHSANS NADHEGFLLG EVRQEETFSI SDSQISNTEF LQVIEIHNHQ PCSKLFSFYD YASKVNEESL DRILKDRRKK VIGWYRFRRN TQQQMSYREQ VLHKQLTRIL GVPDLVFLLF SFISTANNST HALEYVLFRP NRRYNQRISL AIPNLGNTSQ QEYKVSSVPN TSQSYAKVIK EHGTDFFDKD GVMKDIRAIY QVYNALQEKV QAVCADVEKS ERVVESCQAE VNKLRRQITQ RKNEKEQERR LQQAVLS

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Macromolecule #3: BRCC45 (BRE)

MacromoleculeName: BRCC45 (BRE) / type: protein_or_peptide / ID: 3 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: GAMSPEVALN RISPMLSPFI SSVVRNGKVG LDATNCLRIT DLKSGCTSLT PGPNCDRFKL HIPYAGETLK WDIIFNAQYP ELPPDFIFGE DAEFLPDPSA LQNLASWNPS NPECLLLVVK ELVQQYHQFQ CSRLRESSRL MFEYQTLLEE PQYGENMEIY AGKKNNWTGE ...String:
GAMSPEVALN RISPMLSPFI SSVVRNGKVG LDATNCLRIT DLKSGCTSLT PGPNCDRFKL HIPYAGETLK WDIIFNAQYP ELPPDFIFGE DAEFLPDPSA LQNLASWNPS NPECLLLVVK ELVQQYHQFQ CSRLRESSRL MFEYQTLLEE PQYGENMEIY AGKKNNWTGE FSARFLLKLP VDFSNIPTYL LKDVNEDPGE DVALLSVSFE DTEATQVYPK LYLSPRIEHA LGGSSALHIP AFPGGGCLID YVPQVCHLLT NKVQYVIQGY HKRREYIAAF LSHFGTGVVE YDAEGFTKLT LLLMWKDFCF LVHIDLPLFF PRDQPTLTFQ SVYHFTNSGQ LYSQAQKNYP YSPRWDGNEM AKRAKAYFKT FVPQFQEAAF ANGKL

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Macromolecule #4: MERIT40 (BABAM1)

MacromoleculeName: MERIT40 (BABAM1) / type: protein_or_peptide / ID: 4 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: SWQVPPPAPE VQIRTPRVNC PEKVIICLDL SEEMSLPKLE SFNGSKTNAL NVSQKMIEMF VRTKHKIDKS HEFALVVVND DTAWLSGLTS DPRELCSCLY DLETASCSTF NLEGLFSLIQ QKTELPVTEN VQTIPPPYVV RTILVYSRPP CQPQFSLTEP MKKMFQCPYF ...String:
SWQVPPPAPE VQIRTPRVNC PEKVIICLDL SEEMSLPKLE SFNGSKTNAL NVSQKMIEMF VRTKHKIDKS HEFALVVVND DTAWLSGLTS DPRELCSCLY DLETASCSTF NLEGLFSLIQ QKTELPVTEN VQTIPPPYVV RTILVYSRPP CQPQFSLTEP MKKMFQCPYF FFDVVYIHNG TEEKEEEMSW KDMFAFMGSL DTKGTSYKYE VALAGPALEL HNCMAKLLAH PLQRPCQSHA SYSLLEEEDE AIEVEATV

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Macromolecule #5: SHMT2

MacromoleculeName: SHMT2 / type: protein_or_peptide / ID: 5 / Enantiomer: LEVO / EC number: glycine hydroxymethyltransferase
Source (natural)Organism: Homo sapiens (human)
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString: GSGQLVRMAI RAQHSNAAQT QTGEANRGWT GQESLSDSDP EMWELLQREK DRQCRGLELI ASENFCSRAA LEALGSCLNN KYSEGYPGKR YYGGAEVVDE IELLCQRRAL EAFDLDPAQW GVNVQPYSGS PANLAVYTAL LQPHDRIMGL DLPDGGHLTH GYMSDVKRIS ...String:
GSGQLVRMAI RAQHSNAAQT QTGEANRGWT GQESLSDSDP EMWELLQREK DRQCRGLELI ASENFCSRAA LEALGSCLNN KYSEGYPGKR YYGGAEVVDE IELLCQRRAL EAFDLDPAQW GVNVQPYSGS PANLAVYTAL LQPHDRIMGL DLPDGGHLTH GYMSDVKRIS ATSIFFESMP YKLNPKTGLI DYNQLALTAR LFRPRLIIAG TSAYARLIDY ARMREVCDEV KAHLLADMAH ISGLVAAKVI PSPFKHADIV TTTTHKTLRG TRSGLIFYRK GVKAVDPKTG REIPYTFEDR INFAVFPSLQ GGPHNHAIAA VAVALKQACT PMFREYSLQV LKNARAMADA LLERGYSLVS GGTDNHLVLV DLRPKGLDGA RAERVLELVS ITANKNTCPG DRSAITPGGL RLGAPALTSR QFREDDFRRV VDFIDEGVNI GLEVKSKTAK LQDFKSFLLK DSETSQRLAN LRQRVEQFAR AFPMPGFDEH

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

Concentration0.051 mg/mL
BufferpH: 7.5
Component:
ConcentrationNameFormula
25.0 mMHEPES
150.0 mMNaClSodium chloride
1.0 mMTCEP
GridModel: Quantifoil R1.2/1.3 / Material: COPPER
VitrificationCryogen name: ETHANE / Chamber humidity: 95 % / Chamber temperature: 277 K
DetailsSpecimen contained BRCC36, ABRAXAS2, BRCC45, MERIT40 and SHMT2 macromolecules

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsC2 aperture diameter: 70.0 µm / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy / Cs: 2.7 mm / Nominal defocus max: -1.6 µm / Nominal defocus min: -3.1 µm / Nominal magnification: 75000
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN
Image recordingFilm or detector model: FEI FALCON III (4k x 4k) / Detector mode: INTEGRATING / Number grids imaged: 3 / Number real images: 7494 / Average exposure time: 2.0 sec. / Average electron dose: 1.2 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionSoftware - Name: RELION
Startup modelType of model: INSILICO MODEL
Details: Model generated in RELION using SGD from particles from 2D classification.
Initial angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: RELION
Final 3D classificationNumber classes: 4 / Software - Name: RELION
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: RELION
Final reconstructionApplied symmetry - Point group: C2 (2 fold cyclic) / Resolution.type: BY AUTHOR / Resolution: 4.2 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION / Number images used: 64403
FSC plot (resolution estimation)

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Atomic model buiding 1

Initial model(PDB ID:

5cw3

,

6dk3

)
RefinementProtocol: RIGID BODY FIT

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