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- PDB-9fx3: Structure of active human CD109 -

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Basic information

Entry
Database: PDB / ID: 9fx3
TitleStructure of active human CD109
ComponentsCD109 antigen
KeywordsIMMUNE SYSTEM / Protease inhibitor / Protease cleaved / Active conformation / Alfa-macroglobulin
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 / serine-type endopeptidase inhibitor activity / negative regulation of transforming growth factor beta receptor signaling pathway / 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)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.2 Å
AuthorsAlmeida, A.V. / Andersen, G.R.
Funding support Denmark, 1items
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
DepositionJul 1, 2024Deposition site: PDBE / Processing site: PDBE
Revision 1.0Mar 19, 2025Provider: repository / Type: Initial release
Revision 1.0Mar 19, 2025Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Mar 19, 2025Data content type: Half map / Part number: 1 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Mar 19, 2025Data content type: Half map / Part number: 2 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Mar 19, 2025Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Mar 19, 2025Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release
Revision 1.1Sep 17, 2025Group: Data collection / Database references / Category: citation / citation_author / em_admin
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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: CD109 antigen
hetero molecules


Theoretical massNumber of molelcules
Total (without water)143,69612
Polymers140,4501
Non-polymers3,24611
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

#1: Protein CD109 antigen / 150 kDa TGF-beta-1-binding protein / C3 and PZP-like alpha-2-macroglobulin domain-containing ...150 kDa TGF-beta-1-binding protein / C3 and PZP-like alpha-2-macroglobulin domain-containing protein 7 / Platelet-specific Gov antigen / p180 / r150


Mass: 140449.797 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CD109, CPAMD7 / Production host: Homo sapiens (human) / References: UniProt: Q6YHK3
#2: Polysaccharide
2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 424.401 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DGlcpNAcb1-4DGlcpNAcb1-ROHGlycam Condensed SequenceGMML 1.0
WURCS=2.0/1,2,1/[a2122h-1b_1-5_2*NCC/3=O]/1-1/a4-b1WURCSPDB2Glycan 1.1.0
[][D-1-deoxy-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{}}LINUCSPDB-CARE
#3: Sugar
ChemComp-NAG / 2-acetamido-2-deoxy-beta-D-glucopyranose / N-acetyl-beta-D-glucosamine / 2-acetamido-2-deoxy-beta-D-glucose / 2-acetamido-2-deoxy-D-glucose / 2-acetamido-2-deoxy-glucose / N-ACETYL-D-GLUCOSAMINE


Type: D-saccharide, beta linking / Mass: 221.208 Da / Num. of mol.: 7 / Source method: obtained synthetically / Formula: C8H15NO6 / Feature type: SUBJECT OF INVESTIGATION
IdentifierTypeProgram
DGlcpNAcbCONDENSED IUPAC CARBOHYDRATE SYMBOLGMML 1.0
N-acetyl-b-D-glucopyranosamineCOMMON NAMEGMML 1.0
b-D-GlcpNAcIUPAC CARBOHYDRATE SYMBOLPDB-CARE 1.0
GlcNAcSNFG CARBOHYDRATE SYMBOLGMML 1.0
Has ligand of interestY
Has protein modificationY

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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

ComponentName: Monomeric active non-GPI bounded CD109 / Type: RIBOSOME
Details: C-terminal GPI motif (residues 1421-1445) was removed
Entity ID: #1 / Source: RECOMBINANT
Molecular weightValue: 0.165 MDa / Experimental value: YES
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human) / Strain: HEK293 / Plasmid: pcDNA3.1(+)
Buffer solutionpH: 7.4
Buffer component
IDConc.NameFormulaBuffer-ID
120 mMHEPESC8H18N2O4S1
2150 mMSodium ChlorideNaCl1
34 mMCHAPSC32H58N2O7S1
SpecimenConc.: 5 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES / Details: Monodisperse sample
Specimen supportGrid material: GOLD / Grid mesh size: 300 divisions/in. / Grid type: Au-flat 1.2/1.3
VitrificationInstrument: LEICA EM GP / Cryogen 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 defocus max: 1700 nm / Nominal defocus min: 800 nm
Image recordingElectron dose: 59.9 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Num. of grids imaged: 2 / Num. of real images: 7306

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Processing

EM software
IDNameVersionCategory
1cryoSPARC4.04particle selection
2EPUimage acquisition
4cryoSPARC4.04CTF correction
7Coot10model fitting
9PHENIX1.2model refinement
10cryoSPARC4.04initial Euler assignment
11cryoSPARC4.04final Euler assignment
12cryoSPARC4.04classification
13cryoSPARC4.043D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionNum. of particles selected: 1101360
3D reconstructionResolution: 3.2 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 121082 / Num. of class averages: 1 / Symmetry type: POINT
Atomic model buildingProtocol: RIGID BODY FIT
Atomic model buildingAccession code: Q6YHK3 / Source name: AlphaFold / Type: in silico model

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