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- PDB-8sno: Structure of mature human ADAM17/iRhom2 sheddase complex, conform... -

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Basic information

Entry
Database: PDB / ID: 8sno
TitleStructure of mature human ADAM17/iRhom2 sheddase complex, conformation 2
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


regulation of epidermal growth factor receptor signaling pathway / protein transporter activity / CD163 mediating an anti-inflammatory response / growth factor binding / regulation of protein secretion / negative regulation of protein secretion / protein localization to plasma membrane / negative regulation of inflammatory response to antigenic stimulus / Golgi lumen / protein transport ...regulation of epidermal growth factor receptor signaling pathway / protein transporter activity / CD163 mediating an anti-inflammatory response / growth factor binding / regulation of protein secretion / negative regulation of protein secretion / protein localization to plasma membrane / negative regulation of inflammatory response to antigenic stimulus / Golgi lumen / protein transport / endoplasmic reticulum membrane / plasma membrane
Similarity search - Function
Rhomboid serine protease / : / Inactive rhomboid proteins 1/2, N-terminal / Domain of unknown function DUF3850 / Domain of unknown function (DUF3850) / ASCH / Peptidase S54, rhomboid domain / Rhomboid domain / ASCH domain / Rhomboid-like superfamily / PUA-like superfamily
Similarity search - Domain/homology
DUF3850 domain-containing protein / 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 16, 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)161,8463
Polymers161,8062
Non-polymers401
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: 68302.641 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, EC: 3.4.24.86
#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-CA / CALCIUM ION


Mass: 40.078 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Ca
Has ligand of interestN
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: mature human ADAM17/iRhom2 sheddase complex, conformation 2
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: 66.6 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: 325764 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0045828
ELECTRON MICROSCOPYf_angle_d0.7127907
ELECTRON MICROSCOPYf_dihedral_angle_d12.7892102
ELECTRON MICROSCOPYf_chiral_restr0.044868
ELECTRON MICROSCOPYf_plane_restr0.0041015

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