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UniProtKB - O43353 (RIPK2_HUMAN)

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Protein

Receptor-interacting serine/threonine-protein kinase 2

Gene

RIPK2

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

Serine/threonine/tyrosine kinase that plays an essential role in modulation of innate and adaptive immune responses. Upon stimulation by bacterial peptidoglycans, NOD1 and NOD2 are activated, oligomerize and recruit RIPK2 through CARD-CARD domains. Contributes to the tyrosine phosphorylation of the guanine exchange factor ARHGEF2 through Src tyrosine kinase leading to NF-kappaB activation by NOD2. Once recruited, RIPK2 autophosphorylates and undergoes 'Lys-63'-linked polyubiquitination by E3 ubiquitin ligases XIAP, BIRC2 and BIRC3. The polyubiquitinated protein mediates the recruitment of MAP3K7/TAK1 to IKBKG/NEMO and induces 'Lys-63'-linked polyubiquitination of IKBKG/NEMO and subsequent activation of IKBKB/IKKB. In turn, NF-kappa-B is released from NF-kappa-B inhibitors and translocates into the nucleus where it activates the transcription of hundreds of genes involved in immune response, growth control, or protection against apoptosis. Plays also a role during engagement of the T-cell receptor (TCR) in promoting BCL10 phosphorylation and subsequent NF-kappa-B activation.5 Publications

Catalytic activityi

ATP + a protein = ADP + a phosphoprotein.
ATP + a [protein]-L-tyrosine = ADP + a [protein]-L-tyrosine phosphate.PROSITE-ProRule annotation

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Binding sitei47ATP1
Active sitei146Proton acceptor1

Regions

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Nucleotide bindingi24 – 32ATPPROSITE-ProRule annotation9

GO - Molecular functioni

  • ATP binding Source: UniProtKB-KW
  • CARD domain binding Source: MGI
  • identical protein binding Source: IntAct
  • LIM domain binding Source: UniProtKB
  • non-membrane spanning protein tyrosine kinase activity Source: UniProtKB-EC
  • protein homodimerization activity Source: BHF-UCL
  • protein serine/threonine kinase activity Source: GO_Central
  • receptor binding Source: UniProtKB
  • signal transducer activity Source: ProtInc
Complete GO annotation...

GO - Biological processi

Complete GO annotation...

Keywordsi

Molecular functionKinase, Serine/threonine-protein kinase, Transferase
Biological processAdaptive immunity, Apoptosis, Immunity, Innate immunity
LigandATP-binding, Nucleotide-binding

Enzyme and pathway databases

BRENDAi2.7.10.2. 2681.
ReactomeiR-HSA-168638. NOD1/2 Signaling Pathway.
R-HSA-202424. Downstream TCR signaling.
R-HSA-209543. p75NTR recruits signalling complexes.
R-HSA-445989. TAK1 activates NFkB by phosphorylation and activation of IKKs complex.
R-HSA-446652. Interleukin-1 signaling.
R-HSA-450302. activated TAK1 mediates p38 MAPK activation.
R-HSA-450321. JNK (c-Jun kinases) phosphorylation and activation mediated by activated human TAK1.
R-HSA-5689896. Ovarian tumor domain proteases.
SignaLinkiO43353.
SIGNORiO43353.

Names & Taxonomyi

Protein namesi
Recommended name:
Receptor-interacting serine/threonine-protein kinase 2 (EC:2.7.11.1)
Alternative name(s):
CARD-containing interleukin-1 beta-converting enzyme-associated kinase
Short name:
CARD-containing IL-1 beta ICE-kinase
RIP-like-interacting CLARP kinase
Receptor-interacting protein 2
Short name:
RIP-2
Tyrosine-protein kinase RIPK2 (EC:2.7.10.2)
Gene namesi
Name:RIPK2
Synonyms:CARDIAK, RICK, RIP2
ORF Names:UNQ277/PRO314/PRO34092
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo
Proteomesi
  • UP000005640 Componenti: Chromosome 8

Organism-specific databases

HGNCiHGNC:10020. RIPK2.

Subcellular locationi

GO - Cellular componenti

  • cytoplasm Source: UniProtKB
  • cytoskeleton Source: UniProtKB
  • cytosol Source: HPA
  • protein complex Source: UniProtKB
  • vesicle Source: UniProtKB
Complete GO annotation...

Keywords - Cellular componenti

Cytoplasm

Pathology & Biotechi

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi47K → A: Abolishes kinase activity. 2 Publications1
Mutagenesisi47K → M: Reduces FAS-mediated apoptosis. 2 Publications1
Mutagenesisi146D → N: Abolishes kinase activity. 1 Publication1
Mutagenesisi209K → R: Complete loss of polyubiquitination. 1 Publication1
Mutagenesisi381Y → A: Prevents phosphorylation. Reduces serine and threonine phosphorylation of ARHGEF2. 1
Mutagenesisi444R → E: Abolishes interaction with NOD1. 1 Publication1
Mutagenesisi474Y → F: Decreases interaction with NOD2. 1 Publication1
Mutagenesisi483R → E: Abolishes interaction with NOD1. 1 Publication1
Mutagenesisi488R → E: Abolishes interaction with NOD1. 1 Publication1

Organism-specific databases

DisGeNETi8767.
OpenTargetsiENSG00000104312.
PharmGKBiPA34395.

Chemistry databases

ChEMBLiCHEMBL5014.
GuidetoPHARMACOLOGYi2190.

Polymorphism and mutation databases

BioMutaiRIPK2.

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00000866081 – 540Receptor-interacting serine/threonine-protein kinase 2Add BLAST540

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei168PhosphoserineCombined sources1
Modified residuei176Phosphoserine; by autocatalysis1 Publication1
Cross-linki209Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin)1 Publication
Modified residuei363PhosphoserineCombined sources1
Modified residuei381Phosphotyrosine; by CSK1 Publication1
Modified residuei393PhosphoserineCombined sources1
Modified residuei474Phosphotyrosine; by autocatalysis1 Publication1
Modified residuei527PhosphoserineCombined sources1
Modified residuei529PhosphoserineCombined sources1
Modified residuei531PhosphoserineCombined sources1
Modified residuei539PhosphoserineCombined sources1

Post-translational modificationi

Autophosphorylated. Autophosphorylation at Tyr-474 is necessary for effective NOD2 signaling. Phosphorylated. Phosphorylation at Tyr-381 by Src kinase CSK occurs in a ARHGEF2-dependent manner and is required for NOD2-dependent innate immune activation.3 Publications
Ubiquitinated on Lys-209; undergoes 'Lys-63'-linked polyubiquitination catalyzed by ITCH. Polyubiquitinated with 'Lys-48' and 'Lys-63'-linked chains by BIRC2/c-IAP1 and BIRC3/c-IAP2, leading to activation of NF-kappa-B. Also undergoes 'Met-1'-linked polyubiquitination; the head-to-tail linear polyubiquitination is mediated by the LUBAC complex in response to NOD2 stimulation. Linear polyubiquitination is restricted by FAM105B/otulin, probably to limit NOD2-dependent proinflammatory signaling activation of NF-kappa-B.5 Publications

Keywords - PTMi

Isopeptide bond, Phosphoprotein, Ubl conjugation

Proteomic databases

EPDiO43353.
MaxQBiO43353.
PaxDbiO43353.
PeptideAtlasiO43353.
PRIDEiO43353.

PTM databases

iPTMnetiO43353.
PhosphoSitePlusiO43353.

Expressioni

Tissue specificityi

Detected in heart, brain, placenta, lung, peripheral blood leukocytes, spleen, kidney, testis, prostate, pancreas and lymph node.

Gene expression databases

BgeeiENSG00000104312.
CleanExiHS_RIPK2.
ExpressionAtlasiO43353. baseline and differential.
GenevisibleiO43353. HS.

Organism-specific databases

HPAiHPA015273.
HPA016499.

Interactioni

Subunit structurei

Found in a signaling complex consisting of at least ARHGEF2, NOD2 and RIPK2. Interacts with ARHGEF2; the interaction mediates tyrosine phosphorylation of RIPK2 by Src kinase CSK. Binds to CFLAR/CLARP and CASP1 via their CARD domains. Binds to BIRC3/c-IAP1 and BIRC2/c-IAP2, TRAF1, TRAF2, TRAF5 and TRAF6. May be a component of both the TNFRSF1A and TNRFSF5/CD40 receptor complex. Interacts with NOD1. Interacts (via CARD domain) with NOD2 (via CARD domain). Interacts with MAP3K4; this interaction sequesters RIPK2 from the NOD2 signaling pathway. Interacts with IKBKG/NEMO. The polyubiquitinated protein interacts with MAP3K7/TAK1. Interacts with XIAP/BIRC4. Interacts with NLRP10. Interacts with CARD9.7 Publications

Binary interactionsi

Show more details

GO - Molecular functioni

  • CARD domain binding Source: MGI
  • identical protein binding Source: IntAct
  • LIM domain binding Source: UniProtKB
  • protein homodimerization activity Source: BHF-UCL
  • receptor binding Source: UniProtKB
Complete GO annotation...

Protein-protein interaction databases

BioGridi114300. 44 interactors.
DIPiDIP-27518N.
IntActiO43353. 13 interactors.
MINTiMINT-90752.
STRINGi9606.ENSP00000220751.

Chemistry databases

BindingDBiO43353.

Structurei

Secondary structure

1540
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Beta strandi7 – 9Combined sources3
Helixi15 – 17Combined sources3
Beta strandi18 – 25Combined sources8
Beta strandi31 – 37Combined sources7
Turni38 – 40Combined sources3
Beta strandi43 – 48Combined sources6
Helixi59 – 72Combined sources14
Beta strandi81 – 86Combined sources6
Beta strandi91 – 96Combined sources6
Helixi103 – 108Combined sources6
Turni110 – 112Combined sources3
Helixi118 – 136Combined sources19
Beta strandi138 – 140Combined sources3
Helixi149 – 151Combined sources3
Beta strandi152 – 154Combined sources3
Beta strandi160 – 162Combined sources3
Helixi190 – 192Combined sources3
Helixi195 – 197Combined sources3
Turni202 – 204Combined sources3
Helixi210 – 224Combined sources15
Turni228 – 231Combined sources4
Helixi235 – 243Combined sources9
Turni252 – 254Combined sources3
Helixi262 – 272Combined sources11
Helixi277 – 279Combined sources3
Helixi283 – 294Combined sources12
Helixi299 – 307Combined sources9
Helixi436 – 450Combined sources15
Helixi453 – 465Combined sources13
Helixi471 – 476Combined sources6
Helixi483 – 497Combined sources15
Helixi501 – 511Combined sources11
Beta strandi526 – 528Combined sources3
Turni530 – 532Combined sources3

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
2N7ZNMR-A434-539[»]
2N83NMR-B434-539[»]
4C8BX-ray2.75A/B8-317[»]
5AR2X-ray2.44A/B1-310[»]
5AR3X-ray3.23A/B1-310[»]
5AR4X-ray2.70A/B1-310[»]
5AR5X-ray2.66A/B1-310[»]
5AR7X-ray2.71A/B1-310[»]
5AR8X-ray2.79A/B1-310[»]
5J79X-ray2.69A/B1-310[»]
5J7BX-ray2.53A/B1-310[»]
ProteinModelPortaliO43353.
SMRiO43353.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini18 – 294Protein kinasePROSITE-ProRule annotationAdd BLAST277
Domaini432 – 524CARDPROSITE-ProRule annotationAdd BLAST93

Domaini

Contains an N-terminal kinase domain and a C-terminal caspase activation and recruitment domain (CARD) that mediates the recruitment of CARD-containing proteins.

Sequence similaritiesi

Belongs to the protein kinase superfamily. TKL Ser/Thr protein kinase family.Curated

Phylogenomic databases

eggNOGiKOG0192. Eukaryota.
COG0515. LUCA.
GeneTreeiENSGT00550000074536.
HOGENOMiHOG000136856.
HOVERGENiHBG054242.
InParanoidiO43353.
KOiK08846.
OMAiQWIQSKR.
OrthoDBiEOG091G0505.
PhylomeDBiO43353.
TreeFamiTF106506.

Family and domain databases

InterProiView protein in InterPro
IPR001315. CARD.
IPR011029. DEATH-like_dom.
IPR011009. Kinase-like_dom.
IPR000719. Prot_kinase_dom.
IPR017322. Rcpt-int_Ser/Thr_kinase-2.
IPR001245. Ser-Thr/Tyr_kinase_cat_dom.
IPR008271. Ser/Thr_kinase_AS.
PfamiView protein in Pfam
PF00619. CARD. 1 hit.
PF07714. Pkinase_Tyr. 1 hit.
PIRSFiPIRSF037921. STPK_RIP2. 1 hit.
SMARTiView protein in SMART
SM00220. S_TKc. 1 hit.
SUPFAMiSSF47986. SSF47986. 1 hit.
SSF56112. SSF56112. 1 hit.
PROSITEiView protein in PROSITE
PS50209. CARD. 1 hit.
PS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00108. PROTEIN_KINASE_ST. 1 hit.

Sequences (2)i

Sequence statusi: Complete.

This entry describes 2 isoformsi produced by alternative splicing. AlignAdd to basket

Isoform 1 (identifier: O43353-1) [UniParc]FASTAAdd to basket

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

« Hide

        10         20         30         40         50
MNGEAICSAL PTIPYHKLAD LRYLSRGASG TVSSARHADW RVQVAVKHLH 
        60         70         80         90        100
IHTPLLDSER KDVLREAEIL HKARFSYILP ILGICNEPEF LGIVTEYMPN 
       110        120        130        140        150
GSLNELLHRK TEYPDVAWPL RFRILHEIAL GVNYLHNMTP PLLHHDLKTQ 
       160        170        180        190        200
NILLDNEFHV KIADFGLSKW RMMSLSQSRS SKSAPEGGTI IYMPPENYEP 
       210        220        230        240        250
GQKSRASIKH DIYSYAVITW EVLSRKQPFE DVTNPLQIMY SVSQGHRPVI 
       260        270        280        290        300
NEESLPYDIP HRARMISLIE SGWAQNPDER PSFLKCLIEL EPVLRTFEEI 
       310        320        330        340        350
TFLEAVIQLK KTKLQSVSSA IHLCDKKKME LSLNIPVNHG PQEESCGSSQ 
       360        370        380        390        400
LHENSGSPET SRSLPAPQDN DFLSRKAQDC YFMKLHHCPG NHSWDSTISG 
       410        420        430        440        450
SQRAAFCDHK TTPCSSAIIN PLSTAGNSER LQPGIAQQWI QSKREDIVNQ 
       460        470        480        490        500
MTEACLNQSL DALLSRDLIM KEDYELVSTK PTRTSKVRQL LDTTDIQGEE 
       510        520        530        540
FAKVIVQKLK DNKQMGLQPY PEILVVSRSP SLNLLQNKSM
Length:540
Mass (Da):61,195
Last modified:November 1, 1998 - v2
Checksum:i575A692239505792
GO
Isoform 2 (identifier: O43353-2) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     1-137: Missing.

Show »
Length:403
Mass (Da):45,582
Checksum:i9F0DE53A01B25EF5
GO

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti271S → G in BAH13484 (PubMed:14702039).Curated1
Sequence conflicti514Q → R in BAH13484 (PubMed:14702039).Curated1

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_041045259I → T1 PublicationCorresponds to variant dbSNP:rs2230801Ensembl.1
Natural variantiVAR_041046268L → V1 PublicationCorresponds to variant dbSNP:rs35004667Ensembl.1
Natural variantiVAR_041047313K → N1 PublicationCorresponds to variant dbSNP:rs35395048Ensembl.1

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_0132661 – 137Missing in isoform 2. 2 PublicationsAdd BLAST137

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF027706 mRNA. Translation: AAC34970.1.
AF078530 mRNA. Translation: AAC27722.1.
AF064824 mRNA. Translation: AAC25668.1.
AY358813 mRNA. Translation: AAQ89172.1.
AY358814 mRNA. Translation: AAQ89173.1.
AK301448 mRNA. Translation: BAH13484.1.
AC004003 Genomic DNA. Translation: AAC24561.1.
AF117829 Genomic DNA. No translation available.
BC004553 mRNA. Translation: AAH04553.1.
CCDSiCCDS6247.1. [O43353-1]
RefSeqiNP_003812.1. NM_003821.5. [O43353-1]
XP_005251149.1. XM_005251092.3. [O43353-2]
UniGeneiHs.103755.

Genome annotation databases

EnsembliENST00000220751; ENSP00000220751; ENSG00000104312. [O43353-1]
GeneIDi8767.
KEGGihsa:8767.
UCSCiuc003yee.4. human. [O43353-1]

Keywords - Coding sequence diversityi

Alternative splicing, Polymorphism

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.

Entry informationi

Entry nameiRIPK2_HUMAN
AccessioniPrimary (citable) accession number: O43353
Secondary accession number(s): B7Z748, Q6UWF0
Entry historyiIntegrated into UniProtKB/Swiss-Prot: May 2, 2002
Last sequence update: November 1, 1998
Last modified: June 7, 2017
This is version 187 of the entry and version 2 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Miscellaneousi

Keywords - Technical termi

3D-structure, Complete proteome, Reference proteome

Documents

  1. Human chromosome 8
    Human chromosome 8: entries, gene names and cross-references to MIM
  2. Human entries with polymorphisms or disease mutations
    List of human entries with polymorphisms or disease mutations
  3. Human polymorphisms and disease mutations
    Index of human polymorphisms and disease mutations
  4. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  5. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
  6. Human and mouse protein kinases
    Human and mouse protein kinases: classification and index
  7. SIMILARITY comments
    Index of protein domains and families