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- EMDB-33573: Complex of integrin alphaV/beta8, L-TGF-beta1, and LRRC33 at a ra... -

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Basic information

Entry
Database: EMDB / ID: EMD-33573
TitleComplex of integrin alphaV/beta8, L-TGF-beta1, and LRRC33 at a ratio of 2:2:1
Map data
Sample
  • Complex: Complex of integrin alphaV/beta8, L-TGF-beta1, and LRRC33 at a ratio of 2:2:1
    • Protein or peptide: Integrin alphaV
    • Protein or peptide: Integrin beta8
    • Protein or peptide: L-TGF-beta1
    • Protein or peptide: LRRC33
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 5.19 Å
AuthorsDuan Z / Zhang Z
Funding support China, 1 items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)32171201 China
CitationJournal: Nat Commun / Year: 2022
Title: Specificity of TGF-β1 signal designated by LRRC33 and integrin αβ.
Authors: Zelin Duan / Xuezhen Lin / Lixia Wang / Qiuxin Zhen / Yuefeng Jiang / Chuxin Chen / Jing Yang / Chia-Hsueh Lee / Yan Qin / Ying Li / Bo Zhao / Jianchuan Wang / Zhe Zhang /
Abstract: Myeloid lineage cells present the latent form of transforming growth factor-β1 (L-TGF-β1) to the membrane using an anchor protein LRRC33. Integrin αβ activates extracellular L-TGF-β1 to trigger ...Myeloid lineage cells present the latent form of transforming growth factor-β1 (L-TGF-β1) to the membrane using an anchor protein LRRC33. Integrin αβ activates extracellular L-TGF-β1 to trigger the downstream signaling functions. However, the mechanism designating the specificity of TGF-β1 presentation and activation remains incompletely understood. Here, we report cryo-EM structures of human L-TGF-β1/LRRC33 and integrin αβ/L-TGF-β1 complexes. Combined with biochemical and cell-based analyses, we demonstrate that LRRC33 only presents L-TGF-β1 but not the -β2 or -β3 isoforms due to difference of key residues on the growth factor domains. Moreover, we reveal a 2:2 binding mode of integrin αβ and L-TGF-β1, which shows higher avidity and more efficient L-TGF-β1 activation than previously reported 1:2 binding mode. We also uncover that the disulfide-linked loop of the integrin subunit β determines its exquisite affinity to L-TGF-β1. Together, our findings provide important insights into the specificity of TGF-β1 signaling achieved by LRRC33 and integrin αβ.
History
DepositionJun 8, 2022-
Header (metadata) releaseAug 31, 2022-
Map releaseAug 31, 2022-
UpdateSep 7, 2022-
Current statusSep 7, 2022Processing site: PDBj / Status: Released

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Structure visualization

Supplemental images

emd_33573.png

Downloads & links

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Map

FileDownload / File: emd_33573.map.gz / Format: CCP4 / Size: 216 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Voxel sizeX=Y=Z: 1.055 Å
Density
Contour LevelBy AUTHOR: 0.005
Minimum - Maximum-0.005905144 - 0.02463794
Average (Standard dev.)1.7354558e-05 (±0.00096522196)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions384384384
Spacing384384384
CellA=B=C: 405.12 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #1

Fileemd_33573_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #2

Fileemd_33573_half_map_2.map
Projections & Slices
AxesZYX

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Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Complex of integrin alphaV/beta8, L-TGF-beta1, and LRRC33 at a ra...

EntireName: Complex of integrin alphaV/beta8, L-TGF-beta1, and LRRC33 at a ratio of 2:2:1
Components
  • Complex: Complex of integrin alphaV/beta8, L-TGF-beta1, and LRRC33 at a ratio of 2:2:1
    • Protein or peptide: Integrin alphaV
    • Protein or peptide: Integrin beta8
    • Protein or peptide: L-TGF-beta1
    • Protein or peptide: LRRC33

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Supramolecule #1: Complex of integrin alphaV/beta8, L-TGF-beta1, and LRRC33 at a ra...

SupramoleculeName: Complex of integrin alphaV/beta8, L-TGF-beta1, and LRRC33 at a ratio of 2:2:1
type: complex / Chimera: Yes / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)
Recombinant expressionOrganism: Homo sapiens (human)
Molecular weightTheoretical: 400 KDa

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Macromolecule #1: Integrin alphaV

MacromoleculeName: Integrin alphaV / type: protein_or_peptide / ID: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MAFPPRRRLR LGPRGLPLLL SGLLLPLCRA FNLDVDSPAE YSGPEGSYFG FAVDFFVPSA SSRMFLLVGA PKANTTQPGI VEGGQVLKCD WSSTRRCQPI EFDATGNRDY AKDDPLEFKS HQWFGASVRS KQDKILACAP LYHWRTEMKQ EREPVGTCFL QDGTKTVEYA ...String:
MAFPPRRRLR LGPRGLPLLL SGLLLPLCRA FNLDVDSPAE YSGPEGSYFG FAVDFFVPSA SSRMFLLVGA PKANTTQPGI VEGGQVLKCD WSSTRRCQPI EFDATGNRDY AKDDPLEFKS HQWFGASVRS KQDKILACAP LYHWRTEMKQ EREPVGTCFL QDGTKTVEYA PCRSQDIDAD GQGFCQGGFS IDFTKADRVL LGGPGSFYWQ GQLISDQVAE IVSKYDPNVY SIKYNNQLAT RTAQAIFDDS YLGYSVAVGD FNGDGIDDFV SGVPRAARTL GMVYIYDGKN MSSLYNFTGE QMAAYFGFSV AATDINGDDY ADVFIGAPLF MDRGSDGKLQ EVGQVSVSLQ RASGDFQTTK LNGFEVFARF GSAIAPLGDL DQDGFNDIAI AAPYGGEDKK GIVYIFNGRS TGLNAVPSQI LEGQWAARSG CPPSFGYSMK GATDIDKNGY PDLIVGAFGV DRAILYRARP VITVNAGLEV YPSILNQDNK TCSLPGTALK VSCFNVRFCL KADGKGVLPR KLNFQVELLL DKLKQKGAIR RALFLYSRSP SHSKNMTISR GGLMQCEELI AYLRDESEFR DKLTPITIFM EYRLDYRTAA DTTGLQPILN QFTPANISRQ AHILLDTGGL EVLFQGPGEN AQLEKELQAL EKENAQLEWE LQALEKELAQ TTGWRGGHVV EGLAGELEQL RARLEHHPQG QREPAG SNS LEVLFQ

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Macromolecule #2: Integrin beta8

MacromoleculeName: Integrin beta8 / type: protein_or_peptide / ID: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MDMRVPAQLL GLLLLWFSGV LEDNRCASSN AASCARCLAL GPECGWCVQE DFISGGSRSE RCDIVSNLIS KGCSVDSIEY PSVHVIIPTE NEINTQVTPG EVSIQLRPGA EANFMLKVHP LKKYPVDLYY LVDVSASMHN NIEKLNSVGN DLSRKMAFFS RDFRLGFGSY ...String:
MDMRVPAQLL GLLLLWFSGV LEDNRCASSN AASCARCLAL GPECGWCVQE DFISGGSRSE RCDIVSNLIS KGCSVDSIEY PSVHVIIPTE NEINTQVTPG EVSIQLRPGA EANFMLKVHP LKKYPVDLYY LVDVSASMHN NIEKLNSVGN DLSRKMAFFS RDFRLGFGSY VDKTVSPYIS IHPERIHNQC SDYNLDCMPP HGYIHVLSLT ENITEFEKAV HRQKISGNID TPEGGFDAML QAAVCESHIG WRKEAKRLLL VMTDQTSHLA LDSKLAGIVC PNDGNCHLKN NVYVKSTTME HPSLGQLSEK LIDNNINVIF AVQGKQFHWY KDLLPLLPGT IAGEIESKAA NLNNLVVEAY QKLISEVKVQ VENQVQGIYF NITAICPDGS RKPGMEGCRN VTSNDEVLFN VTVTMKKCDV TGGKNYAIIK PIGFNETAKI HIHRNCSCQC EDNRGPKGKC VDETFLDSKC FQCDENK

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Macromolecule #3: L-TGF-beta1

MacromoleculeName: L-TGF-beta1 / type: protein_or_peptide / ID: 3 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MPLLLLLPLL WAGALALSTC KTIDMELVKR KRIEAIRGQI LSKLRLASPP SQGEVPPGPL PEAVLALYNS TRDRVAGESA EPEPEPEADY YAKEVTRVLM VETHNEIYDK FKQSTHSIYM FFNTSELREA VPEPVLLSRA ELRLLRLKLK VEQHVELYQK YSNNSWRYLS ...String:
MPLLLLLPLL WAGALALSTC KTIDMELVKR KRIEAIRGQI LSKLRLASPP SQGEVPPGPL PEAVLALYNS TRDRVAGESA EPEPEPEADY YAKEVTRVLM VETHNEIYDK FKQSTHSIYM FFNTSELREA VPEPVLLSRA ELRLLRLKLK VEQHVELYQK YSNNSWRYLS NRLLAPSDSP EWLSFDVTGV VRQWLSRGGE IEGFRLSAHC SCDSRDNTLQ VDINGFTTGR RGDLATIHGM NRPFLLLMAT PLERAQHLQS SRHRRALDTN YCFSSTEKNC CVRQLYIDFR KDLGWKWIHE PKGYHANFCL GPCPYIWSLD TQYSKVLALY NQHNPGASAA PCCVPQALEP LPIVYYVGRK PKVEQLSNMI VRSCKCS

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Macromolecule #4: LRRC33

MacromoleculeName: LRRC33 / type: protein_or_peptide / ID: 4 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MPLLLLLPLL WAGALAWRNR SGTATAASQG VCKLVGGAAD CRGQSLASVP SSLPPHARML TLDANPLKTL WNHSLQPYPL LESLSLHSCH LERISRGAFQ EQGHLRSLVL GDNCLSENYE ETAAALHALP GLRRLDLSGN ALTEDMAALM LQNLSSLRSV SLAGNTIMRL ...String:
MPLLLLLPLL WAGALAWRNR SGTATAASQG VCKLVGGAAD CRGQSLASVP SSLPPHARML TLDANPLKTL WNHSLQPYPL LESLSLHSCH LERISRGAFQ EQGHLRSLVL GDNCLSENYE ETAAALHALP GLRRLDLSGN ALTEDMAALM LQNLSSLRSV SLAGNTIMRL DDSVFEGLER LRELDLQRNY IFEIEGGAFD GLAELRHLNL AFNNLPCIVD FGLTRLRVLN VSYNVLEWFL ATGGEAAFEL ETLDLSHNQL LFFPLLPQYS KLRTLLLRDN NMGFYRDLYN TSSPREMVAQ FLLVDGNVTN ITTVSLWEEF SSSDLADLRF LDMSQNQFQY LPDGFLRKMP SLSHLNLHQN CLMTLHIREH EPPGALTELD LSHNQLSELH LAPGLASCLG SLRLFNLSSN QLLGVPPGLF ANARNITTLD MSHNQISLCP LPAASDRVGP PSCVDFRNMA SLRSLSLEGC GLGALPDCPF QGTSLTYLDL SSNWGVLNGS LAPLQDVAPM LQVLSLRNMG LHSSFMALDF SGFGNLRDLD LSGNCLTTFP RFGGSLALET LDLRRNSLTA LPQKAVSEQL SRGLRTIYLS QNPYDCCGVD GWGALQHGQT VADWAMVTCN LSSKIIRVTE LPGGVPRDCK WERLDLG SN SLEVLFQ

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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

Concentration3 mg/mL
BufferpH: 7.5
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy / Nominal defocus max: 1.2 µm / Nominal defocus min: 0.8 µm
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Detector mode: SUPER-RESOLUTION / Average electron dose: 60.0 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Initial angle assignmentType: NOT APPLICABLE
Final angle assignmentType: ANGULAR RECONSTITUTION
Final reconstructionResolution.type: BY AUTHOR / Resolution: 5.19 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 410538

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Atomic model buiding 1

RefinementProtocol: OTHER

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