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- PDB-8snl: Structure of human ADAM17/iRhom2 sheddase complex -

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Basic information

Entry
Database: PDB / ID: 8snl
TitleStructure of human ADAM17/iRhom2 sheddase complex
Components
  • Disintegrin and metalloproteinase domain-containing protein 17
  • Inactive rhomboid protein 2
KeywordsMEMBRANE PROTEIN/HYDROLASE / Membrane protein complex / MEMBRANE PROTEIN / MEMBRANE PROTEIN-HYDROLASE complex
Function / homology
Function and homology information


ADAM 17 endopeptidase / regulation of mast cell apoptotic process / signal release / metalloendopeptidase activity involved in amyloid precursor protein catabolic process / cellular response to high density lipoprotein particle stimulus / regulation of epidermal growth factor receptor signaling pathway / production of molecular mediator involved in inflammatory response / Constitutive Signaling by NOTCH1 t(7;9)(NOTCH1:M1580_K2555) Translocation Mutant / Notch receptor processing / tumor necrosis factor binding ...ADAM 17 endopeptidase / regulation of mast cell apoptotic process / signal release / metalloendopeptidase activity involved in amyloid precursor protein catabolic process / cellular response to high density lipoprotein particle stimulus / regulation of epidermal growth factor receptor signaling pathway / production of molecular mediator involved in inflammatory response / Constitutive Signaling by NOTCH1 t(7;9)(NOTCH1:M1580_K2555) Translocation Mutant / Notch receptor processing / tumor necrosis factor binding / interleukin-6 receptor binding / positive regulation of T cell chemotaxis / protein transporter activity / TNF signaling / cytokine precursor processing / positive regulation of leukocyte chemotaxis / Release of Hh-Np from the secreting cell / Regulated proteolysis of p75NTR / regulation of axon regeneration / metallodipeptidase activity / commissural neuron axon guidance / regulation of neuron migration / positive regulation of tumor necrosis factor-mediated signaling pathway / germinal center formation / neutrophil mediated immunity / Notch binding / wound healing, spreading of epidermal cells / positive regulation of vascular endothelial cell proliferation / negative regulation of cold-induced thermogenesis / cell adhesion mediated by integrin / CD163 mediating an anti-inflammatory response / regulation of protein secretion / growth factor binding / ERBB2-EGFR signaling pathway / amyloid precursor protein catabolic process / Signaling by EGFR / cytokine binding / Collagen degradation / membrane protein ectodomain proteolysis / negative regulation of protein secretion / positive regulation of blood vessel endothelial cell migration / Growth hormone receptor signaling / Nuclear signaling by ERBB4 / positive regulation of G1/S transition of mitotic cell cycle / positive regulation of epidermal growth factor receptor signaling pathway / spleen development / positive regulation of chemokine production / Notch signaling pathway / B cell differentiation / Constitutive Signaling by NOTCH1 HD Domain Mutants / Activated NOTCH1 Transmits Signal to the Nucleus / protein localization to plasma membrane / PDZ domain binding / cell motility / phosphatidylinositol 3-kinase/protein kinase B signal transduction / negative regulation of inflammatory response to antigenic stimulus / negative regulation of transforming growth factor beta receptor signaling pathway / protein processing / metalloendopeptidase activity / SH3 domain binding / Golgi lumen / integrin binding / Constitutive Signaling by NOTCH1 PEST Domain Mutants / Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants / epidermal growth factor receptor signaling pathway / metallopeptidase activity / positive regulation of tumor necrosis factor production / T cell differentiation in thymus / peptidase activity / protein transport / negative regulation of neuron projection development / actin cytoskeleton / positive regulation of cell growth / endopeptidase activity / response to lipopolysaccharide / response to hypoxia / cell adhesion / apical plasma membrane / defense response to Gram-positive bacterium / positive regulation of cell migration / membrane raft / response to xenobiotic stimulus / endoplasmic reticulum lumen / Golgi membrane / positive regulation of cell population proliferation / endoplasmic reticulum membrane / cell surface / proteolysis / membrane / metal ion binding / plasma membrane / cytoplasm / cytosol
Similarity search - Function
Rhomboid serine protease / : / Inactive rhomboid proteins 1/2, N-terminal / ADAM17, membrane-proximal domain / Membrane-proximal domain, switch, for ADAM17 / ADAM10/ADAM17 catalytic domain / : / Metallo-peptidase family M12B Reprolysin-like / Peptidase S54, rhomboid domain / Rhomboid domain ...Rhomboid serine protease / : / Inactive rhomboid proteins 1/2, N-terminal / ADAM17, membrane-proximal domain / Membrane-proximal domain, switch, for ADAM17 / ADAM10/ADAM17 catalytic domain / : / Metallo-peptidase family M12B Reprolysin-like / Peptidase S54, rhomboid domain / Rhomboid domain / Rhomboid-like superfamily / Disintegrin / Disintegrin domain profile. / Homologues of snake disintegrins / Disintegrin domain / Disintegrin domain superfamily / Peptidase M12B, ADAM/reprolysin / ADAM type metalloprotease domain profile. / Metallopeptidase, catalytic domain superfamily / Neutral zinc metallopeptidases, zinc-binding region signature.
Similarity search - Domain/homology
Disintegrin and metalloproteinase domain-containing protein 17 / Inactive rhomboid protein 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.78 Å
AuthorsZhao, H. / Dai, Y. / Wang, Y. / Lee, C.H.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R01GM143282 United States
CitationJournal: Mol Cell / Year: 2024
Title: Cryo-EM reveals that iRhom2 restrains ADAM17 protease activity to control the release of growth factor and inflammatory signals.
Authors: Fangfang Lu / Hongtu Zhao / Yaxin Dai / Yingdi Wang / Chia-Hsueh Lee / Matthew Freeman /
Abstract: A disintegrin and metalloprotease 17 (ADAM17) is a membrane-tethered protease that triggers multiple signaling pathways. It releases active forms of the primary inflammatory cytokine tumor necrosis ...A disintegrin and metalloprotease 17 (ADAM17) is a membrane-tethered protease that triggers multiple signaling pathways. It releases active forms of the primary inflammatory cytokine tumor necrosis factor (TNF) and cancer-implicated epidermal growth factor (EGF) family growth factors. iRhom2, a rhomboid-like, membrane-embedded pseudoprotease, is an essential cofactor of ADAM17. Here, we present cryoelectron microscopy (cryo-EM) structures of the human ADAM17/iRhom2 complex in both inactive and active states. These reveal three regulatory mechanisms. First, exploiting the rhomboid-like hallmark of TMD recognition, iRhom2 interacts with the ADAM17 TMD to promote ADAM17 trafficking and enzyme maturation. Second, a unique iRhom2 extracellular domain unexpectedly retains the cleaved ADAM17 inhibitory prodomain, safeguarding against premature activation and dysregulated proteolysis. Finally, loss of the prodomain from the complex mobilizes the ADAM17 protease domain, contributing to its ability to engage substrates. Our results reveal how a rhomboid-like pseudoprotease has been repurposed during evolution to regulate a potent membrane-tethered enzyme, ADAM17, ensuring the fidelity of inflammatory and growth factor signaling.
History
DepositionApr 27, 2023Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 29, 2024Provider: repository / Type: Initial release
Revision 1.1Oct 30, 2024Group: Data collection / Structure summary
Category: em_admin / pdbx_entry_details / pdbx_modification_feature
Item: _em_admin.last_update / _pdbx_entry_details.has_protein_modification
Revision 1.2Dec 11, 2024Group: Data collection / Database references / Category: citation / citation_author / em_admin
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _em_admin.last_update

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Disintegrin and metalloproteinase domain-containing protein 17
B: Inactive rhomboid protein 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)186,7514
Polymers186,6452
Non-polymers1052
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein Disintegrin and metalloproteinase domain-containing protein 17 / ADAM 17 / Snake venom-like protease / TNF-alpha convertase / TNF-alpha-converting enzyme


Mass: 93141.930 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ADAM17, CSVP, TACE / Production host: Homo sapiens (human) / References: UniProt: P78536, ADAM 17 endopeptidase
#2: Protein Inactive rhomboid protein 2 / iRhom2 / Rhomboid 5 homolog 2 / Rhomboid family member 2 / Rhomboid veinlet-like protein 5 / ...iRhom2 / Rhomboid 5 homolog 2 / Rhomboid family member 2 / Rhomboid veinlet-like protein 5 / Rhomboid veinlet-like protein 6


Mass: 93503.258 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: RHBDF2, IRHOM2, RHBDL5, RHBDL6 / Production host: Homo sapiens (human) / References: UniProt: Q6PJF5
#3: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Zn / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical ChemComp-CA / CALCIUM ION


Mass: 40.078 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Ca
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: human ADAM17/iRhom2 sheddase complex / Type: COMPLEX / Entity ID: #1-#2 / Source: RECOMBINANT
Molecular weightExperimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 8
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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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: OTHER
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 1600 nm / Nominal defocus min: 600 nm
Image recordingElectron dose: 79.8 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

EM softwareName: PHENIX / Version: 1.18.2_3874: / Category: model refinement
CTF correctionType: NONE
3D reconstructionResolution: 2.78 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 229986 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0049313
ELECTRON MICROSCOPYf_angle_d0.73812618
ELECTRON MICROSCOPYf_dihedral_angle_d12.9973396
ELECTRON MICROSCOPYf_chiral_restr0.0451381
ELECTRON MICROSCOPYf_plane_restr0.0061626

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