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- EMDB-19699: Structure of native human CD109 -

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Basic information

Entry
Database: EMDB / ID: EMD-19699
TitleStructure of native human CD109
Map data
Sample
  • Complex: Monomeric native non-GPI bounded CD109
    • Protein or peptide: CD109 antigen
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
KeywordsProtease inhibitor / Native conformation / Alfa-macroglobulin / IMMUNE SYSTEM
Function / homology
Function and homology information


osteoclast fusion / regulation of keratinocyte differentiation / Post-translational modification: synthesis of GPI-anchored proteins / negative regulation of wound healing / platelet alpha granule membrane / keratinocyte proliferation / hair follicle development / negative regulation of keratinocyte proliferation / negative regulation of stem cell proliferation / side of membrane ...osteoclast fusion / regulation of keratinocyte differentiation / Post-translational modification: synthesis of GPI-anchored proteins / negative regulation of wound healing / platelet alpha granule membrane / keratinocyte proliferation / hair follicle development / negative regulation of keratinocyte proliferation / negative regulation of stem cell proliferation / side of membrane / stem cell proliferation / negative regulation of transforming growth factor beta receptor signaling pathway / serine-type endopeptidase inhibitor activity / Platelet degranulation / cell surface / extracellular space / extracellular region / plasma membrane / cytosol
Similarity search - Function
Alpha-2-macroglobulin, TED domain / Alpha-2-macroglobulin, conserved site / Alpha-2-macroglobulin family thiolester region signature. / : / Alpha-macro-globulin thiol-ester bond-forming region / Alpha-macroglobulin, receptor-binding / Alpha-macroglobulin, receptor-binding domain superfamily / Macroglobulin domain MG3 / : / A-macroglobulin receptor binding domain ...Alpha-2-macroglobulin, TED domain / Alpha-2-macroglobulin, conserved site / Alpha-2-macroglobulin family thiolester region signature. / : / Alpha-macro-globulin thiol-ester bond-forming region / Alpha-macroglobulin, receptor-binding / Alpha-macroglobulin, receptor-binding domain superfamily / Macroglobulin domain MG3 / : / A-macroglobulin receptor binding domain / Macroglobulin domain MG3 / A-macroglobulin receptor / Alpha-2-macroglobulin / Macroglobulin domain / Alpha-2-macroglobulin, bait region domain / Alpha-macroglobulin-like, TED domain / Alpha-2-macroglobulin family / MG2 domain / A-macroglobulin TED domain / Alpha-2-macroglobulin bait region domain / Alpha-2-Macroglobulin / Alpha-2-macroglobulin family / Terpenoid cyclases/protein prenyltransferase alpha-alpha toroid / Immunoglobulin E-set / Immunoglobulin-like fold
Similarity search - Domain/homology
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.99 Å
AuthorsAlmeida VA / Andersen GR
Funding support Denmark, 1 items
OrganizationGrant numberCountry
Danish Council for Independent ResearchDFF-2032-00111B Denmark
CitationJournal: Cell Rep / Year: 2025
Title: Three cryo-EM structures of CD109 reveal its mechanism of protease inhibition.
Authors: Ana V Almeida / Kathrine T Jensen / Seandean L Harwood / Martin H Jørgensen / Nadia S Nielsen / Ida B Thøgersen / Jan J Enghild / Gregers R Andersen /
Abstract: CD109 is a glycosylphosphatidylinositol-anchored protein. In addition to regulating transforming growth factor β (TGF-β) network signaling, CD109 is also a protease inhibitor. Protease cleavage of ...CD109 is a glycosylphosphatidylinositol-anchored protein. In addition to regulating transforming growth factor β (TGF-β) network signaling, CD109 is also a protease inhibitor. Protease cleavage of its bait region triggers a conformational change releasing the major fragment from the cell surface, exposing a reactive thioester that can conjugate proteases. To understand this protease inhibition mechanism, we determined cryoelectron microscopy structures of CD109 in native, protease-activated, and methylamine-activated conformations. Despite CD109's low sequence similarity with the protease inhibitor A2ML1, CD109 adopts a similar protease-activated conformation, suggesting a shared mechanism of protease inhibition. Deglycosylation of CD109 does not affect chymotrypsin conjugation but enhances substrate access, suggesting that CD109 glycans contribute to protease inhibition. Our data provide a structural basis for understanding CD109's protease-triggered membrane release, its protease inhibitory mechanism, and additional biological functions.
History
DepositionFeb 20, 2024-
Header (metadata) releaseMar 5, 2025-
Map releaseMar 5, 2025-
UpdateSep 17, 2025-
Current statusSep 17, 2025Processing site: PDBe / Status: Released

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Structure visualization

Supplemental images

emd_19699.png

Downloads & links

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Map

FileDownload / File: emd_19699.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.29 Å/pix.
x 256 pix.
= 330.24 Å		1.29 Å/pix.
x 256 pix.
= 330.24 Å		1.29 Å/pix.
x 256 pix.
= 330.24 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.29 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.24
Minimum - Maximum-0.58941424 - 1.3665311
Average (Standard dev.)-0.00076981855 (±0.025126046)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 330.24 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #1

Fileemd_19699_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_19699_half_map_2.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Monomeric native non-GPI bounded CD109

EntireName: Monomeric native non-GPI bounded CD109
Components
  • Complex: Monomeric native non-GPI bounded CD109
    • Protein or peptide: CD109 antigen
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose

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Supramolecule #1: Monomeric native non-GPI bounded CD109

SupramoleculeName: Monomeric native non-GPI bounded CD109 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Details: C-terminal GPI motif (residues 1421-1445) was removed
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 165 KDa

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Macromolecule #1: CD109 antigen

MacromoleculeName: CD109 antigen / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 161.851125 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: SVSGWSHPQF EKGGGSGGGS GGSAWSHPQF EKGENLYFQS GSVAPGPRFL VTAPGIIRPG GNVTIGVELL EHCPSQVTVK AELLKTASN LTVSVLEAEG VFEKGSFKTL TLPSLPLNSA DEIYELRVTG RTQDEILFSN STRLSFETKR ISVFIQTDKA L YKPKQEVK ...String:
SVSGWSHPQF EKGGGSGGGS GGSAWSHPQF EKGENLYFQS GSVAPGPRFL VTAPGIIRPG GNVTIGVELL EHCPSQVTVK AELLKTASN LTVSVLEAEG VFEKGSFKTL TLPSLPLNSA DEIYELRVTG RTQDEILFSN STRLSFETKR ISVFIQTDKA L YKPKQEVK FRIVTLFSDF KPYKTSLNIL IKDPKSNLIQ QWLSQQSDLG VISKTFQLSS HPILGDWSIQ VQVNDQTYYQ SF QVSEYVL PKFEVTLQTP LYCSMNSKHL NGTITAKYTY GKPVKGDVTL TFLPLSFWGK KKNITKTFKI NGSANFSFND EEM KNVMDS SNGLSEYLDL SSPGPVEILT TVTESVTGIS RNVSTNVFFK QHDYIIEFFD YTTVLKPSLN FTATVKVTRA DGNQ LTLEE RRNNVVITVT QRNYTEYWSG SNSGNQKMEA VQKINYTVPQ SGTFKIEFPI LEDSSELQLK AYFLGSKSSM AVHSL FKSP SKTYIQLKTR DENIKVGSPF ELVVSGNKRL KELSYMVVSR GQLVAVGKQN STMFSLTPEN SWTPKACVIV YYIEDD GEI ISDVLKIPVQ LVFKNKIKLY WSKVKAEPSE KVSLRISVTQ PDSIVGIVAV DKSVNLMNAS NDITMENVVH ELELYNT GY YLGMFMNSFA VFQECGLWVL TDANLTKDYI DGVYDNAEYA ERFMEENEGH IVDIHDFSLG SSPHVRKHFP ETWIWLDT N MGYRIYQEFE VTVPDSITSW VATGFVISED LGLGLTTTPV ELQAFQPFFI FLNLPYSVIR GEEFALEITI FNYLKDATE VKVIIEKSDK FDILMTSNEI NATGHQQTLL VPSEDGATVL FPIRPTHLGE IPITVTALSP TASDAVTQMI LVKAEGIEKS YSQSILLDL TDNRLQSTLK TLSFSFPPNT VTGSERVQIT AIGDVLGPSI NGLASLIRMP YGCGEQNMIN FAPNIYILDY L TKKKQLTD NLKEKALSFM RQGYQRELLY QREDGSFSAF GNYDPSGSTW LSAFVLRCFL EADPYIDIDQ NVLHRTYTWL KG HQKSNGE FWDPGRVIHS ELQGGNKSPV TLTAYIVTSL LGYRKYQPNI DVQESIHFLE SEFSRGISDN YTLALITYAL SSV GSPKAK EALNMLTWRA EQEGGMQFWV SSESKLSDSW QPRSLDIEVA AYALLSHFLQ FQTSEGIPIM RWLSRQRNSL GGFA STQDT TVALKALSEF AALMNTERTN IQVTVTGPSS PSPVKFLIDT HNRLLLQTAE LAVVQPTAVN ISANGFGFAI CQLNV VYNV KASGSSRRRR SIQNQEAFDL DVAVKENKDD LNHVDLNVCT SFSGPGRSGM ALMEVNLLSG FMVPSEAISL SETVKK VEY DHGKLNLYLD SVNETQFCVN IPAVRNFKVS NTQDASVSIV DYYEPRRQAV RSYNSEVKLS SCDLCSDVQG CRPCEDG AH HHHHH

UniProtKB: CD109 antigen

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Macromolecule #3: 2-acetamido-2-deoxy-beta-D-glucopyranose

MacromoleculeName: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 3 / Number of copies: 4 / Formula: NAG
Molecular weightTheoretical: 221.208 Da
Chemical component information

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

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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

Concentration5.0 mg/mL
BufferpH: 7.4
Component:
ConcentrationFormulaName
20.0 mMC8H18N2O4SHEPES
150.0 mMNaClSodium Chloride
6.0 mMC32H58N2O7SCHAPS
GridModel: Au-flat 1.2/1.3 / Material: GOLD / Mesh: 300 / Support film - Material: GOLD / Support film - topology: CONTINUOUS / Support film - Film thickness: 1200 / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Time: 45 sec. / Pretreatment - Atmosphere: AIR
VitrificationCryogen name: ETHANE / Chamber humidity: 95 % / Chamber temperature: 279.15 K / Instrument: LEICA EM GP
DetailsMonodisperse sample

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Number grids imaged: 2 / Number real images: 9975 / Average electron dose: 59.9 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 1.7 µm / Nominal defocus min: 0.8 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 5307660
CTF correctionSoftware - Name: cryoSPARC (ver. 4.04) / Type: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: NONE
Final reconstructionNumber classes used: 1 / Applied symmetry - Point group: C1 (asymmetric) / Resolution.type: BY AUTHOR / Resolution: 2.99 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC (ver. 4.04) / Number images used: 273564
Initial angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC (ver. 4.04)
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC (ver. 4.04)
Final 3D classificationNumber classes: 2 / Avg.num./class: 1997065 / Software - Name: cryoSPARC (ver. 4.04)
FSC plot (resolution estimation)

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Atomic model buiding 1

Initial modelPDB ID:

yhk3


Chain - Chain ID: A / Chain - Source name: AlphaFold / Chain - Initial model type: in silico model
RefinementProtocol: RIGID BODY FIT
Output model

PDB-8s3o:
Structure of native human CD109

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