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- EMDB-15757: Structure of RIP2K dimer bound to the XIAP BIR2 domain -

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Basic information

Entry
Database: EMDB / ID: EMD-15757
TitleStructure of RIP2K dimer bound to the XIAP BIR2 domain
Map datacryo EM map of RIP2 kinase dimer with bound the BIR2 domain of E3 ligase XIAP
Sample
  • Complex: dimeric RIP2K bound to XIAP BIR2 domain
    • Complex: RIP2K dimer
      • Protein or peptide: Receptor-interacting serine/threonine-protein kinase 2
    • Complex: BIR2 domain of E3 ligase XIAP
      • Protein or peptide: E3 ubiquitin-protein ligase XIAP
  • Ligand: ZINC ION
Keywordskinase / BIR2 / complex / dimer / IMMUNE SYSTEM
Function / homology
Function and homology information


response to interleukin-18 / positive regulation of T-helper 1 cell differentiation / toll-like receptor 2 signaling pathway / endopeptidase regulator activity / positive regulation of cytokine-mediated signaling pathway / regulation of apoptosis involved in tissue homeostasis / inhibition of cysteine-type endopeptidase activity / positive regulation of protein linear polyubiquitination / regulation of BMP signaling pathway / immature T cell proliferation in thymus ...response to interleukin-18 / positive regulation of T-helper 1 cell differentiation / toll-like receptor 2 signaling pathway / endopeptidase regulator activity / positive regulation of cytokine-mediated signaling pathway / regulation of apoptosis involved in tissue homeostasis / inhibition of cysteine-type endopeptidase activity / positive regulation of protein linear polyubiquitination / regulation of BMP signaling pathway / immature T cell proliferation in thymus / positive regulation of T-helper 1 type immune response / LIM domain binding / positive regulation of xenophagy / CD4-positive, alpha-beta T cell proliferation / copper ion homeostasis / xenophagy / nucleotide-binding oligomerization domain containing 1 signaling pathway / positive regulation of protein K63-linked ubiquitination / regulation of nucleotide-binding domain, leucine rich repeat containing receptor signaling pathway / cellular response to muramyl dipeptide / caspase binding / positive regulation of immature T cell proliferation in thymus / CARD domain binding / JUN kinase kinase kinase activity / positive regulation of CD4-positive, alpha-beta T cell proliferation / cellular response to peptidoglycan / response to interleukin-12 / protein serine/threonine kinase binding / activation of cysteine-type endopeptidase activity / nucleotide-binding oligomerization domain containing 2 signaling pathway / SMAC, XIAP-regulated apoptotic response / Regulation of the apoptosome activity / Activation of caspases through apoptosome-mediated cleavage / SMAC (DIABLO) binds to IAPs / SMAC(DIABLO)-mediated dissociation of IAP:caspase complexes / positive regulation of macrophage cytokine production / TNFR1-induced proapoptotic signaling / regulation of innate immune response / RIPK1-mediated regulated necrosis / toll-like receptor 4 signaling pathway / cysteine-type endopeptidase inhibitor activity / response to exogenous dsRNA / protein K63-linked ubiquitination / positive regulation of interferon-alpha production / cysteine-type endopeptidase inhibitor activity involved in apoptotic process / cellular response to lipoteichoic acid / positive regulation of type I interferon production / negative regulation of tumor necrosis factor-mediated signaling pathway / canonical NF-kappaB signal transduction / signaling adaptor activity / positive regulation of chemokine production / JNK cascade / lipopolysaccharide-mediated signaling pathway / ERK1 and ERK2 cascade / p75NTR recruits signalling complexes / positive regulation of interleukin-2 production / positive regulation of interferon-beta production / positive regulation of interleukin-12 production / Regulation of PTEN localization / response to interleukin-1 / JNK (c-Jun kinases) phosphorylation and activation mediated by activated human TAK1 / positive regulation of peptidyl-threonine phosphorylation / TNFR1-induced NF-kappa-B signaling pathway / positive regulation of protein ubiquitination / positive regulation of interleukin-1 beta production / activated TAK1 mediates p38 MAPK activation / Deactivation of the beta-catenin transactivating complex / Regulation of TNFR1 signaling / positive regulation of JNK cascade / non-specific protein-tyrosine kinase / TAK1-dependent IKK and NF-kappa-B activation / RING-type E3 ubiquitin transferase / NOD1/2 Signaling Pathway / non-membrane spanning protein tyrosine kinase activity / protein homooligomerization / negative regulation of cysteine-type endopeptidase activity involved in apoptotic process / Regulation of necroptotic cell death / Wnt signaling pathway / Regulation of PTEN stability and activity / positive regulation of interleukin-6 production / Interleukin-1 signaling / cytokine-mediated signaling pathway / ubiquitin-protein transferase activity / positive regulation of canonical Wnt signaling pathway / ubiquitin protein ligase activity / positive regulation of peptidyl-tyrosine phosphorylation / Ovarian tumor domain proteases / positive regulation of type II interferon production / positive regulation of tumor necrosis factor production / Downstream TCR signaling / positive regulation of peptidyl-serine phosphorylation / positive regulation of NF-kappaB transcription factor activity / regulation of cell population proliferation / positive regulation of protein binding / regulation of inflammatory response / T cell receptor signaling pathway / neuron apoptotic process / regulation of apoptotic process / positive regulation of canonical NF-kappaB signal transduction / vesicle
Similarity search - Function
Receptor-interacting serine/threonine-protein kinase 2 / RIP2, CARD domain / XIAP/BIRC8, UBA domain / : / BIRC2/3-like, UBA domain / BIR repeat. / BIR repeat / Inhibitor of Apoptosis domain / BIR repeat profile. / Baculoviral inhibition of apoptosis protein repeat ...Receptor-interacting serine/threonine-protein kinase 2 / RIP2, CARD domain / XIAP/BIRC8, UBA domain / : / BIRC2/3-like, UBA domain / BIR repeat. / BIR repeat / Inhibitor of Apoptosis domain / BIR repeat profile. / Baculoviral inhibition of apoptosis protein repeat / CARD domain / CARD caspase recruitment domain profile. / Caspase recruitment domain / Zinc finger, C3HC4 type (RING finger) / Death-like domain superfamily / Ring finger / Zinc finger RING-type profile. / Zinc finger, RING-type / Protein tyrosine and serine/threonine kinase / Serine-threonine/tyrosine-protein kinase, catalytic domain / Serine/threonine-protein kinase, active site / Serine/Threonine protein kinases active-site signature. / Serine/Threonine protein kinases, catalytic domain / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily
Similarity search - Domain/homology
Receptor-interacting serine/threonine-protein kinase 2 / E3 ubiquitin-protein ligase XIAP
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.15 Å
AuthorsPellegrini E / Cusack S
Funding support1 items
OrganizationGrant numberCountry
Not funded
CitationJournal: Life Sci Alliance / Year: 2023
Title: Structure shows that the BIR2 domain of E3 ligase XIAP binds across the RIPK2 kinase dimer interface.
Authors: Mathilde Lethier / Karine Huard / Michael Hons / Adrien Favier / Bernhard Brutscher / Elisabetta Boeri Erba / Derek W Abbott / Stephen Cusack / Erika Pellegrini /
Abstract: RIPK2 is an essential adaptor for NOD signalling and its kinase domain is a drug target for NOD-related diseases, such as inflammatory bowel disease. However, recent work indicates that the ...RIPK2 is an essential adaptor for NOD signalling and its kinase domain is a drug target for NOD-related diseases, such as inflammatory bowel disease. However, recent work indicates that the phosphorylation activity of RIPK2 is dispensable for signalling and that inhibitors of both RIPK2 activity and RIPK2 ubiquitination prevent the essential interaction between RIPK2 and the BIR2 domain of XIAP, the key RIPK2 ubiquitin E3 ligase. Moreover, XIAP BIR2 antagonists also block this interaction. To reveal the molecular mechanisms involved, we combined native mass spectrometry, NMR, and cryo-electron microscopy to determine the structure of the RIPK2 kinase BIR2 domain complex and validated the interface with in cellulo assays. The structure shows that BIR2 binds across the RIPK2 kinase antiparallel dimer and provides an explanation for both inhibitory mechanisms. It also highlights why phosphorylation of the kinase activation loop is dispensable for signalling while revealing the structural role of RIPK2-K209 residue in the RIPK2-XIAP BIR2 interaction. Our results clarify the features of the RIPK2 conformation essential for its role as a scaffold protein for ubiquitination.
History
DepositionSep 5, 2022-
Header (metadata) releaseOct 26, 2022-
Map releaseOct 26, 2022-
UpdateSep 20, 2023-
Current statusSep 20, 2023Processing site: PDBe / Status: Released

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Structure visualization

Supplemental images

emd_15757.png

Downloads & links

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Map

FileDownload / File: emd_15757.map.gz / Format: CCP4 / Size: 103 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Annotationcryo EM map of RIP2 kinase dimer with bound the BIR2 domain of E3 ligase XIAP
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.83 Å/pix.
x 300 pix.
= 248.1 Å		0.83 Å/pix.
x 300 pix.
= 248.1 Å		0.83 Å/pix.
x 300 pix.
= 248.1 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.827 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.125
Minimum - Maximum-0.45508128 - 1.1479805
Average (Standard dev.)-0.0013349224 (±0.025402075)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions300300300
Spacing300300300
CellA=B=C: 248.1 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_15757_msk_1.map
Projections & Slices
AxesZYX

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Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Additional map: map sharpen at -100 A2

Fileemd_15757_additional_1.map
Annotationmap sharpen at -100 A2
Projections & Slices
AxesZYX

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Density Histograms

Histogram

Histogram (log scale)

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Half map: #2

Fileemd_15757_half_map_1.map
Projections & Slices
AxesZYX

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Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #1

Fileemd_15757_half_map_2.map
Projections & Slices
AxesZYX

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Histogram

Histogram (log scale)

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Sample components

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Entire : dimeric RIP2K bound to XIAP BIR2 domain

EntireName: dimeric RIP2K bound to XIAP BIR2 domain
Components
  • Complex: dimeric RIP2K bound to XIAP BIR2 domain
    • Complex: RIP2K dimer
      • Protein or peptide: Receptor-interacting serine/threonine-protein kinase 2
    • Complex: BIR2 domain of E3 ligase XIAP
      • Protein or peptide: E3 ubiquitin-protein ligase XIAP
  • Ligand: ZINC ION

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Supramolecule #1: dimeric RIP2K bound to XIAP BIR2 domain

SupramoleculeName: dimeric RIP2K bound to XIAP BIR2 domain / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#2

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Supramolecule #2: RIP2K dimer

SupramoleculeName: RIP2K dimer / type: complex / ID: 2 / Parent: 1 / Macromolecule list: #2
Source (natural)Organism: Homo sapiens (human)

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Supramolecule #3: BIR2 domain of E3 ligase XIAP

SupramoleculeName: BIR2 domain of E3 ligase XIAP / type: complex / ID: 3 / Parent: 1 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: E3 ubiquitin-protein ligase XIAP

MacromoleculeName: E3 ubiquitin-protein ligase XIAP / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO / EC number: RING-type E3 ubiquitin transferase
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 10.229517 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString:
YPRNPAMYSE EARLKSFQNW PDYAHLTPRE LASAGLYYTG IGDQVQCFCC GGKLKNWEPC DRAWSEHRRH FPNCFFVLGR NLNIRSE

UniProtKB: E3 ubiquitin-protein ligase XIAP

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Macromolecule #2: Receptor-interacting serine/threonine-protein kinase 2

MacromoleculeName: Receptor-interacting serine/threonine-protein kinase 2
type: protein_or_peptide / ID: 2 / Number of copies: 2 / Enantiomer: LEVO / EC number: non-specific serine/threonine protein kinase
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 36.412879 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MNGEAICSAL PTIPYHKLAD LRYLSRGASG TVSSARHADW RVQVAVKHLH IHTPLLDSER KDVLREAEIL HKARFSYILP ILGICNEPE FLGIVTEYMP NGSLNELLHR KTEYPDVAWP LRFRILHEIA LGVNYLHNMT PPLLHHDLKT QNILLDNEFH V KIADFGLS ...String:
MNGEAICSAL PTIPYHKLAD LRYLSRGASG TVSSARHADW RVQVAVKHLH IHTPLLDSER KDVLREAEIL HKARFSYILP ILGICNEPE FLGIVTEYMP NGSLNELLHR KTEYPDVAWP LRFRILHEIA LGVNYLHNMT PPLLHHDLKT QNILLDNEFH V KIADFGLS KWRMMSLSQS RSSKSAPEGG TIIYMPPENY EPGQKSRASI KHDIYSYAVI TWEVLSRKQP FEDVTNPLQI MY SVSQGHR PVINEESLPY DIPHRARMIS LIESGWAQNP DERPSFLKCL IELEPVLRTF EEITFLEAVI QLKKTKLQSV

UniProtKB: Receptor-interacting serine/threonine-protein kinase 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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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

BufferpH: 7.5
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: OTHER / Imaging mode: BRIGHT FIELDBright-field microscopy / Nominal defocus max: 2.5 µm / Nominal defocus min: 0.8 µm / Nominal magnification: 165000
Image recordingFilm or detector model: GATAN K2 QUANTUM (4k x 4k) / Average electron dose: 46.7 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: PDB ENTRY
PDB model - PDB ID:

5ng0


Details: Other IDs used: 4C8B,4J3Y
Initial angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC (ver. 3.3.2)
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC (ver. 3.3.2)
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.15 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC (ver. 3.3.2) / Number images used: 173600
FSC plot (resolution estimation)

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Atomic model buiding 1

RefinementSpace: REAL / Protocol: RIGID BODY FIT
Output model

PDB-8aza:
Structure of RIP2K dimer bound to the XIAP BIR2 domain

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