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- EMDB-40628: Structure of human ADAM17/iRhom2 sheddase complex -

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Basic information

Entry
Database: EMDB / ID: EMD-40628
TitleStructure of human ADAM17/iRhom2 sheddase complex
Map data
Sample
  • Complex: human ADAM17/iRhom2 sheddase complex
    • Protein or peptide: Disintegrin and metalloproteinase domain-containing protein 17
    • Protein or peptide: Inactive rhomboid protein 2
  • Ligand: ZINC ION
  • Ligand: CALCIUM ION
KeywordsMembrane 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 / positive regulation of epidermal growth factor-activated receptor activity / 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 / Constitutive Signaling by NOTCH1 t(7;9)(NOTCH1:M1580_K2555) Translocation Mutant / Notch receptor processing / interleukin-6 receptor binding ...ADAM 17 endopeptidase / regulation of mast cell apoptotic process / signal release / positive regulation of epidermal growth factor-activated receptor activity / 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 / Constitutive Signaling by NOTCH1 t(7;9)(NOTCH1:M1580_K2555) Translocation Mutant / Notch receptor processing / interleukin-6 receptor binding / tumor necrosis factor binding / protein transporter activity / positive regulation of T cell chemotaxis / TNF signaling / positive regulation of leukocyte chemotaxis / Release of Hh-Np from the secreting cell / Regulated proteolysis of p75NTR / commissural neuron axon guidance / positive regulation of tumor necrosis factor-mediated signaling pathway / neutrophil mediated immunity / germinal center formation / Notch binding / wound healing, spreading of epidermal cells / positive regulation of vascular endothelial cell proliferation / negative regulation of cold-induced thermogenesis / CD163 mediating an anti-inflammatory response / positive regulation of epidermal growth factor receptor signaling pathway / cell adhesion mediated by integrin / regulation of protein secretion / Signaling by EGFR / growth factor binding / amyloid precursor protein catabolic process / cytokine binding / Collagen degradation / membrane protein ectodomain proteolysis / positive regulation of blood vessel endothelial cell migration / positive regulation of G1/S transition of mitotic cell cycle / negative regulation of protein secretion / Growth hormone receptor signaling / Nuclear signaling by ERBB4 / positive regulation of chemokine production / spleen development / Notch signaling pathway / Constitutive Signaling by NOTCH1 HD Domain Mutants / B cell differentiation / Activated NOTCH1 Transmits Signal to the Nucleus / protein localization to plasma membrane / PDZ domain binding / phosphatidylinositol 3-kinase/protein kinase B signal transduction / cell motility / 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 / 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 / integrin binding / protein transport / peptidase activity / actin cytoskeleton / T cell differentiation in thymus / positive regulation of cell growth / endopeptidase activity / response to lipopolysaccharide / response to hypoxia / defense response to Gram-positive bacterium / cell adhesion / positive regulation of cell migration / apical plasma membrane / membrane raft / endoplasmic reticulum lumen / response to xenobiotic stimulus / Golgi membrane / positive regulation of cell population proliferation / endoplasmic reticulum membrane / cell surface / proteolysis / metal ion binding / membrane / plasma membrane / cytosol / cytoplasm
Similarity search - Function
Rhomboid serine protease / : / Inactive rhomboid proteins 1/2, N-terminal / ADAM17, membrane-proximal domain / Membrane-proximal domain, switch, for ADAM17 / Metallo-peptidase family M12 / ADAM10/ADAM17 catalytic domain / : / 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 / Metallo-peptidase family M12 / ADAM10/ADAM17 catalytic domain / : / 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)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.78 Å
AuthorsZhao H / Dai Y / Wang Y / Lee CH
Funding support United States, 1 items
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, 2023-
Header (metadata) releaseMay 29, 2024-
Map releaseMay 29, 2024-
UpdateDec 11, 2024-
Current statusDec 11, 2024Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_40628.png

Downloads & links

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Map

FileDownload / File: emd_40628.map.gz / Format: CCP4 / Size: 216 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.83 Å/pix.
x 384 pix.
= 317.184 Å		0.83 Å/pix.
x 384 pix.
= 317.184 Å		0.83 Å/pix.
x 384 pix.
= 317.184 Å

Surface

Projections

Slices (1/3)

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Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.826 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.65
Minimum - Maximum-2.592002 - 4.321769
Average (Standard dev.)0.0010626906 (±0.07075308)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions384384384
Spacing384384384
CellA=B=C: 317.184 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_40628_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #1

Fileemd_40628_half_map_2.map
Projections & Slices
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Histogram

Histogram (log scale)

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Sample components

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Entire : human ADAM17/iRhom2 sheddase complex

EntireName: human ADAM17/iRhom2 sheddase complex
Components
  • Complex: human ADAM17/iRhom2 sheddase complex
    • Protein or peptide: Disintegrin and metalloproteinase domain-containing protein 17
    • Protein or peptide: Inactive rhomboid protein 2
  • Ligand: ZINC ION
  • Ligand: CALCIUM ION

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Supramolecule #1: human ADAM17/iRhom2 sheddase complex

SupramoleculeName: human ADAM17/iRhom2 sheddase complex / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#2
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Disintegrin and metalloproteinase domain-containing protein 17

MacromoleculeName: Disintegrin and metalloproteinase domain-containing protein 17
type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO / EC number: ADAM 17 endopeptidase
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 93.14193 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MRQSLLFLTS VVPFVLAPRP PDDPGFGPHQ RLEKLDSLLS DYDILSLSNI QQHSVRKRDL QTSTHVETLL TFSALKRHFK LYLTSSTER FSQNFKVVVV DGKNESEYTV KWQDFFTGHV VGEPDSRVLA HIRDDDVIIR INTDGAEYNI EPLWRFVNDT K DKRMLVYK ...String:
MRQSLLFLTS VVPFVLAPRP PDDPGFGPHQ RLEKLDSLLS DYDILSLSNI QQHSVRKRDL QTSTHVETLL TFSALKRHFK LYLTSSTER FSQNFKVVVV DGKNESEYTV KWQDFFTGHV VGEPDSRVLA HIRDDDVIIR INTDGAEYNI EPLWRFVNDT K DKRMLVYK SEDIKNVSRL QSPKVCGYLK VDNEELLPKG LVDREPPEEL VHRVKRRADP DPMKNTCKLL VVADHRFYRY MG RGEESTT TNYLIELIDR VDDIYRNTSW DNAGFKGYGI QIEQIRILKS PQEVKPGEKH YNMAKSYPNE EKDAWDVKML LEQ FSFDIA EEASKVCLAH LFTYQDFDMG TLGLAYVGSP RANSHGGVCP KAYYSPVGKK NIYLNSGLTS TKNYGKTILT KEAD LVTTH ELGHNFGAEH DPDGLAECAP NEDQGGKYVM YPIAVSGDHE NNKMFSNCSK QSIYKTIESK AQECFQERSN KVCGN SRVD EGEECDPGIM YLNNDTCCNS DCTLKEGVQC SDRNSPCCKN CQFETAQKKC QEAINATCKG VSYCTGNSSE CPPPGN AED DTVCLDLGKC KDGKCIPFCE REQQLESCAC NETDNSCKVC CRDLSGRCVP YVDAEQKNLF LRKGKPCTVG FCDMNGK CE KRVQDVIERF WDFIDQLSIN TFGKFLADNI VGSVLVFSLI FWIPFSILVH CVDKKLDKQY ESLSLFHPSN VEMLSSMD S ASVRIIKPFP APQTPGRLQP APVIPSAPAA PKLDHQRMDT IQEDPSTDSH MDEDGFEKDP FPNSSTAAKS FEDLTDHPV TRSEKAASFK LQRQNRVDSK ETEC

UniProtKB: Disintegrin and metalloproteinase domain-containing protein 17

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Macromolecule #2: Inactive rhomboid protein 2

MacromoleculeName: Inactive rhomboid protein 2 / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 93.503258 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MASADKNGGS VSSVSSSRLQ SRKPPNLSIT IPPPEKETQA PGEQDSMLPE RKNPAYLKSV SLQEPRSRWQ ESSEKRPGFR RQASLSQSI RKGAAQWFGV SGDWEGQRQQ WQRRSLHHCS MRYGRLKASC QRDLELPSQE APSFQGTESP KPCKMPKIVD P LARGRAFR ...String:
MASADKNGGS VSSVSSSRLQ SRKPPNLSIT IPPPEKETQA PGEQDSMLPE RKNPAYLKSV SLQEPRSRWQ ESSEKRPGFR RQASLSQSI RKGAAQWFGV SGDWEGQRQQ WQRRSLHHCS MRYGRLKASC QRDLELPSQE APSFQGTESP KPCKMPKIVD P LARGRAFR HPEEMDRPHA PHPPLTPGVL SLTSFTSVRS GYSHLPRRKR MSVAHMSLQA AAALLKGRSV LDATGQRCRV VK RSFAFPS FLEEDVVDGA DTFDSSFFSK EEMSSMPDDV FESPPLSASY FRGIPHSASP VSPDGVQIPL KEYGRAPVPG PRR GKRIAS KVKHFAFDRK KRHYGLGVVG NWLNRSYRRS ISSTVQRQLE SFDSHRPYFT YWLTFVHVII TLLVICTYGI APVG FAQHV TTQLVLRNKG VYESVKYIQQ ENFWVGPSSI DLIHLGAKFS PCIRKDGQIE QLVLRERDLE RDSGCCVQND HSGCI QTQR KDCSETLATF VKWQDDTGPP MDKSDLGQKR TSGAVCHQDP RTCEEPASSG AHIWPDDITK WPICTEQARS NHTGFL HMD CEIKGRPCCI GTKGSCEITT REYCEFMHGY FHEEATLCSQ VHCLDKVCGL LPFLNPEVPD QFYRLWLSLF LHAGVVH CL VSVVFQMTIL RDLEKLAGWH RIAIIFILSG ITGNLASAIF LPYRAEVGPA GSQFGLLACL FVELFQSWPL LERPWKAF L NLSAIVLFLF ICGLLPWIDN IAHIFGFLSG LLLAFAFLPY ITFGTSDKYR KRALILVSLL AFAGLFAALV LWLYIYPIN WPWIEHLTCF PFTSRFCEKY ELDQVLH

UniProtKB: Inactive rhomboid protein 2

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Macromolecule #3: ZINC ION

MacromoleculeName: ZINC ION / type: ligand / ID: 3 / Number of copies: 1 / Formula: ZN
Molecular weightTheoretical: 65.409 Da

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Macromolecule #4: CALCIUM ION

MacromoleculeName: CALCIUM ION / type: ligand / ID: 4 / Number of copies: 1 / Formula: CA
Molecular weightTheoretical: 40.078 Da

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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

BufferpH: 8
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 79.8 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: OTHER / Imaging mode: BRIGHT FIELD / Nominal defocus max: 1.6 µm / Nominal defocus min: 0.6 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: OTHER
Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.78 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 229986
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD

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