P57078 (RIPK4_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Receptor-interacting serine/threonine-protein kinase 4
EC=2.7.11.1

Alternative name(s):
Ankyrin repeat domain-containing protein 3
PKC-delta-interacting protein kinase

Gene names

Name:	RIPK4
Synonyms:	ANKRD3, DIK

Organism

Homo sapiens (Human) [Reference proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Primates › Haplorrhini › Simiiformes › Catarrhini › Hominoidea › Hominidae › Homininae › Homo

Protein attributes

Sequence length	832 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	Involved in stratified epithelial development. It is a direct transcriptional target of TP63. Plays a role in NF-kappa-B activation. Ref.3 Ref.5
Catalytic activity	ATP + a protein = ADP + a phosphoprotein.
Subunit structure	Interacts with PRKCB By similarity. Interacts with TRAF1, TRAF2, TRAF3 and TRAF5. Interacts with BIRC2/c-IAP1, BIRC3/c-IAP2 and XIAP/BIRC4. Ref.3 Ref.4
Subcellular location	Cytoplasm. Membrane; Peripheral membrane protein By similarity.
Post-translational modification	May be phosphorylated by MAP3K2 and MAP3K3 By similarity. Proteolytically cleaved by during Fas-induced apoptosis. Cleavage at Asp-388 and Asp-426. Ref.3 Polyubiquitinated with 'Lys-48' and 'Lys-63'-linked chains by BIRC2/c-IAP1 and BIRC3/c-IAP2, leading to activation of NF-kappa-B.
Involvement in disease	Popliteal pterygium syndrome, lethal type (PPS-L) [MIM:263650]: An autosomal recessive disorder characterized by multiple popliteal pterygia leading to severe arthrogryposis, ankyloblepharon filiforme adnatum, filiform bands between the jaws, synostosis of the carpal/tarsal and phalangeal bones in the hands and feet, digital hypoplasia/aplasia, complete soft-tissue syndactyly, lack of nails, lack of scalp hair, eyebrows and eyelashes, blepharophimosis, cleft lip and/or palate, and hypoplastic external genitalia. Early lethality is common, although survival into childhood and beyond has been reported. Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.5 Ref.7
Sequence similarities	Belongs to the protein kinase superfamily. TKL Ser/Thr protein kinase family. Contains 10 ANK repeats. Contains 1 protein kinase domain.

Ontologies

Keywords
Cellular component	Cytoplasm Membrane
Coding sequence diversity	Alternative splicing Polymorphism
Disease	Disease mutation
Domain	ANK repeat Repeat
Ligand	ATP-binding Nucleotide-binding
Molecular function	Kinase Receptor Serine/threonine-protein kinase Transferase
PTM	Isopeptide bond Phosphoprotein Ubl conjugation
Technical term	Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	morphogenesis of an epithelium Inferred from mutant phenotype Ref.5. Source: UniProtKB
Cellular_component	cytoplasm Inferred from sequence or structural similarity. Source: UniProtKB membrane Inferred from electronic annotation. Source: UniProtKB-SubCell
Molecular_function	ATP binding Inferred from electronic annotation. Source: UniProtKB-KW protein serine/threonine kinase activity Inferred from electronic annotation. Source: UniProtKB-KW
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
BIRC2	Q13490	3	EBI-4422308,EBI-514538
BIRC3	Q13489	3	EBI-4422308,EBI-517709
XIAP	P98170	2	EBI-4422308,EBI-517127

Alternative products

This entry describes 2 isoforms produced by alternative splicing. [Align] [Select]

Isoform 1 (identifier: P57078-1)

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.

Isoform 2 (identifier: P57078-2)

The sequence of this isoform differs from the canonical sequence as follows:
     278-325: Missing.

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	1 – 832	832	Receptor-interacting serine/threonine-protein kinase 4		PRO_0000086613
Regions
	Domain	22 – 286	265	Protein kinase
	Repeat	485 – 514	30	ANK 1
	Repeat	518 – 547	30	ANK 2
	Repeat	551 – 580	30	ANK 3
	Repeat	584 – 613	30	ANK 4
	Repeat	617 – 647	31	ANK 5
	Repeat	651 – 680	30	ANK 6
	Repeat	684 – 713	30	ANK 7
	Repeat	717 – 746	30	ANK 8
	Repeat	750 – 780	31	ANK 9
	Repeat	782 – 811	30	ANK 10
	Nucleotide binding	28 – 36	9	ATP By similarity
Sites
	Active site	143	1	Proton acceptor By similarity
	Binding site	51	1	ATP By similarity
	Site	388 – 389	2	Cleavage
	Site	426 – 427	2	Cleavage
Amino acid modifications
	Cross-link	51		Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin) Ref.4
	Cross-link	145		Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin) Ref.4
Natural variations
	Alternative sequence	278 – 325	48	Missing in isoform 2.		VSP_004862
	Natural variant	12	1	A → G. Corresponds to variant rs6586239 [ dbSNP | Ensembl ].		VAR_030160
	Natural variant	81	1	I → N in PPS-L. Ref.5		VAR_067331
	Natural variant	121	1	I → N in PPS-L; loss of function. Ref.7		VAR_067332
	Natural variant	177	1	S → N. Corresponds to variant rs12482626 [ dbSNP | Ensembl ].		VAR_030161
	Natural variant	184	1	T → I in PPS-L; loss of function. Ref.7		VAR_067333
	Natural variant	462	1	I → N. Ref.6		VAR_041050
	Natural variant	463	1	V → M. Ref.6		VAR_041051
	Natural variant	562	1	N → Y. Ref.6		VAR_041052
	Natural variant	669	1	R → H. Ref.6		VAR_041053
	Natural variant	749	1	P → S. Ref.6		VAR_041054
Experimental info
	Sequence conflict	714	1	M → V in BAB56136. Ref.1

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 [UniParc]. Last modified December 1, 2000. Version 1. Checksum: 5D8FFFD5F04F7ECB	FASTA	832	91,611
	10 20 30 40 50 60 MEGDGGTPWA LALLRTFDAG EFTGWEKVGS GGFGQVYKVR HVHWKTWLAI KCSPSLHVDD 70 80 90 100 110 120 RERMELLEEA KKMEMAKFRY ILPVYGICRE PVGLVMEYME TGSLEKLLAS EPLPWDLRFR 130 140 150 160 170 180 IIHETAVGMN FLHCMAPPLL HLDLKPANIL LDAHYHVKIS DFGLAKCNGL SHSHDLSMDG 190 200 210 220 230 240 LFGTIAYLPP ERIREKSRLF DTKHDVYSFA IVIWGVLTQK KPFADEKNIL HIMVKVVKGH 250 260 270 280 290 300 RPELPPVCRA RPRACSHLIR LMQRCWQGDP RVRPTFQGNG LNGELIRQVL AALLPVTGRW 310 320 330 340 350 360 RSPGEGFRLE SEVIIRVTCP LSSPQEITSE TEDLCEKPDD EVKETAHDLD VKSPPEPRSE 370 380 390 400 410 420 VVPARLKRAS APTFDNDYSL SELLSQLDSG VSQAVEGPEE LSRSSSESKL PSSGSGKRLS 430 440 450 460 470 480 GVSSVDSAFS SRGSLSLSFE REPSTSDLGT TDVQKKKLVD AIVSGDTSKL MKILQPQDVD 490 500 510 520 530 540 LALDSGASLL HLAVEAGQEE CAKWLLLNNA NPNLSNRRGS TPLHMAVERR VRGVVELLLA 550 560 570 580 590 600 RKISVNAKDE DQWTALHFAA QNGDESSTRL LLEKNASVNE VDFEGRTPMH VACQHGQENI 610 620 630 640 650 660 VRILLRRGVD VSLQGKDAWL PLHYAAWQGH LPIVKLLAKQ PGVSVNAQTL DGRTPLHLAA 670 680 690 700 710 720 QRGHYRVARI LIDLCSDVNV CSLLAQTPLH VAAETGHTST ARLLLHRGAG KEAMTSDGYT 730 740 750 760 770 780 ALHLAARNGH LATVKLLVEE KADVLARGPL NQTALHLAAA HGHSEVVEEL VSADVIDLFD 790 800 810 820 830 EQGLSALHLA AQGRHAQTVE TLLRHGAHIN LQSLKFQGGH GPAATLLRRS KT
	Isoform 2 [UniParc]. Checksum: EEE7DBD53135AA91	FASTA	784	86,441
	10 20 30 40 50 60 MEGDGGTPWA LALLRTFDAG EFTGWEKVGS GGFGQVYKVR HVHWKTWLAI KCSPSLHVDD 70 80 90 100 110 120 RERMELLEEA KKMEMAKFRY ILPVYGICRE PVGLVMEYME TGSLEKLLAS EPLPWDLRFR 130 140 150 160 170 180 IIHETAVGMN FLHCMAPPLL HLDLKPANIL LDAHYHVKIS DFGLAKCNGL SHSHDLSMDG 190 200 210 220 230 240 LFGTIAYLPP ERIREKSRLF DTKHDVYSFA IVIWGVLTQK KPFADEKNIL HIMVKVVKGH 250 260 270 280 290 300 RPELPPVCRA RPRACSHLIR LMQRCWQGDP RVRPTFQEIT SETEDLCEKP DDEVKETAHD 310 320 330 340 350 360 LDVKSPPEPR SEVVPARLKR ASAPTFDNDY SLSELLSQLD SGVSQAVEGP EELSRSSSES 370 380 390 400 410 420 KLPSSGSGKR LSGVSSVDSA FSSRGSLSLS FEREPSTSDL GTTDVQKKKL VDAIVSGDTS 430 440 450 460 470 480 KLMKILQPQD VDLALDSGAS LLHLAVEAGQ EECAKWLLLN NANPNLSNRR GSTPLHMAVE 490 500 510 520 530 540 RRVRGVVELL LARKISVNAK DEDQWTALHF AAQNGDESST RLLLEKNASV NEVDFEGRTP 550 560 570 580 590 600 MHVACQHGQE NIVRILLRRG VDVSLQGKDA WLPLHYAAWQ GHLPIVKLLA KQPGVSVNAQ 610 620 630 640 650 660 TLDGRTPLHL AAQRGHYRVA RILIDLCSDV NVCSLLAQTP LHVAAETGHT STARLLLHRG 670 680 690 700 710 720 AGKEAMTSDG YTALHLAARN GHLATVKLLV EEKADVLARG PLNQTALHLA AAHGHSEVVE 730 740 750 760 770 780 ELVSADVIDL FDEQGLSALH LAAQGRHAQT VETLLRHGAH INLQSLKFQG GHGPAATLLR RSKT

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	Shimizu N., Kudoh J., Shibuya K. Submitted (AUG-2000) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2). Tissue: Fetal kidney and Fetal lung.
[2]	"The DNA sequence of human chromosome 21." Hattori M., Fujiyama A., Taylor T.D., Watanabe H., Yada T., Park H.-S., Toyoda A., Ishii K., Totoki Y., Choi D.-K., Groner Y., Soeda E., Ohki M., Takagi T., Sakaki Y., Taudien S., Blechschmidt K., Polley A. , Menzel U., Delabar J., Kumpf K., Lehmann R., Patterson D., Reichwald K., Rump A., Schillhabel M., Schudy A., Zimmermann W., Rosenthal A., Kudoh J., Shibuya K., Kawasaki K., Asakawa S., Shintani A., Sasaki T., Nagamine K., Mitsuyama S., Antonarakis S.E., Minoshima S., Shimizu N., Nordsiek G., Hornischer K., Brandt P., Scharfe M., Schoen O., Desario A., Reichelt J., Kauer G., Bloecker H., Ramser J., Beck A., Klages S., Hennig S., Riesselmann L., Dagand E., Wehrmeyer S., Borzym K., Gardiner K., Nizetic D., Francis F., Lehrach H., Reinhardt R., Yaspo M.-L. Nature 405:311-319(2000) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[3]	"RIP4 (DIK/PKK), a novel member of the RIP kinase family, activates NF-kappa B and is processed during apoptosis." Meylan E., Martinon F., Thome M., Gschwendt M., Tschopp J. EMBO Rep. 3:1201-1208(2002) [PubMed] [Europe PMC] [Abstract] Cited for: CLEAVAGE AT ASP-388 AND ASP-426, INTERACTION WITH TRAF1; TRAF2; TRAF3 AND TRAF5, FUNCTION.
[4]	"cIAP1/2 are direct E3 ligases conjugating diverse types of ubiquitin chains to receptor interacting proteins kinases 1 to 4 (RIP1-4)." Bertrand M.J., Lippens S., Staes A., Gilbert B., Roelandt R., De Medts J., Gevaert K., Declercq W., Vandenabeele P. PLoS ONE 6:E22356-E22356(2011) [PubMed] [Europe PMC] [Abstract] Cited for: UBIQUITINATION AT LYS-51 AND LYS-145, UBIQUITINATION BY BIRC2/C-IAP1 AND BIRC3/C-IAP2, INTERACTION WITH BIRC2/C-IAP1; BIRC3/C-IAP2 AND XIAP/BIRC4.
[5]	"Exome sequence identifies RIPK4 as the Bartsocas-Papas syndrome locus." Mitchell K., O'Sullivan J., Missero C., Blair E., Richardson R., Anderson B., Antonini D., Murray J.C., Shanske A.L., Schutte B.C., Romano R.A., Sinha S., Bhaskar S.S., Black G.C., Dixon J., Dixon M.J. Am. J. Hum. Genet. 90:69-75(2012) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, VARIANT PPS-L ASN-81.
[6]	"Patterns of somatic mutation in human cancer genomes." Greenman C., Stephens P., Smith R., Dalgliesh G.L., Hunter C., Bignell G., Davies H., Teague J., Butler A., Stevens C., Edkins S., O'Meara S., Vastrik I., Schmidt E.E., Avis T., Barthorpe S., Bhamra G., Buck G. , Choudhury B., Clements J., Cole J., Dicks E., Forbes S., Gray K., Halliday K., Harrison R., Hills K., Hinton J., Jenkinson A., Jones D., Menzies A., Mironenko T., Perry J., Raine K., Richardson D., Shepherd R., Small A., Tofts C., Varian J., Webb T., West S., Widaa S., Yates A., Cahill D.P., Louis D.N., Goldstraw P., Nicholson A.G., Brasseur F., Looijenga L., Weber B.L., Chiew Y.-E., DeFazio A., Greaves M.F., Green A.R., Campbell P., Birney E., Easton D.F., Chenevix-Trench G., Tan M.-H., Khoo S.K., Teh B.T., Yuen S.T., Leung S.Y., Wooster R., Futreal P.A., Stratton M.R. Nature 446:153-158(2007) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANTS [LARGE SCALE ANALYSIS] ASN-462; MET-463; TYR-562; HIS-669 AND SER-749.
[7]	"Mutations in RIPK4 cause the autosomal-recessive form of popliteal pterygium syndrome." Kalay E., Sezgin O., Chellappa V., Mutlu M., Morsy H., Kayserili H., Kreiger E., Cansu A., Toraman B., Abdalla E.M., Aslan Y., Pillai S., Akarsu N.A. Am. J. Hum. Genet. 90:76-85(2012) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANTS PPS-L ASN-121 AND ILE-184, CHARACTERIZATION OF VARIANTS PPS-L ASN-121 AND ILE-184.
+	Additional computationally mapped references.

Cross-references

Sequence databases
EMBL GenBank DDBJ	AB047783 mRNA. Translation: BAB56136.1. AP001743 Genomic DNA. Translation: BAA95526.1.
IPI	IPI00025714. IPI00215935.
UniGene	Hs.517310.
3D structure databases
ProteinModelPortal	P57078.
ModBase	Search...
Protein-protein interaction databases
IntAct	P57078. 4 interactions.
STRING	9606.ENSP00000332454.
PTM databases
PhosphoSite	P57078.
Polymorphism databases
DMDM	10719883.
Proteomic databases
PaxDb	P57078.
PRIDE	P57078.
Protocols and materials databases
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
Ensembl	ENST00000332512; ENSP00000332454; ENSG00000183421. ENST00000352483; ENSP00000330161; ENSG00000183421.
UCSC	uc002yzn.1. human.
Organism-specific databases
GeneCards	GC21M043159.
HGNC	HGNC:496. RIPK4.
HPA	HPA021158.
MIM	263650. phenotype. 605706. gene.
neXtProt	NX_P57078.
Orphanet	1234. Bartsocas-Papas syndrome.
GenAtlas	Search...
Phylogenomic databases
eggNOG	COG0515.
HOGENOM	HOG000294086.
HOVERGEN	HBG061582.
InParanoid	P57078.
OMA	DLRFRII.
PhylomeDB	P57078.
Gene expression databases
ArrayExpress	P57078.
Bgee	P57078.
CleanEx	HS_RIPK4.
Genevestigator	P57078.
GermOnline	ENSG00000183421. Homo sapiens.
Family and domain databases
Gene3D	1.25.40.20. 4 hits.
InterPro	IPR002110. Ankyrin_rpt. IPR020683. Ankyrin_rpt-contain_dom. IPR011009. Kinase-like_dom. IPR000719. Prot_kinase_cat_dom. IPR017441. Protein_kinase_ATP_BS. IPR008271. Ser/Thr_kinase_AS. [Graphical view]
Pfam	PF00023. Ank. 1 hit. PF12796. Ank_2. 4 hits. PF00069. Pkinase. 1 hit. [Graphical view]
PRINTS	PR01415. ANKYRIN.
SMART	SM00248. ANK. 10 hits. [Graphical view]
SUPFAM	SSF48403. ANK. 1 hit. SSF56112. Kinase_like. 1 hit.
PROSITE	PS50297. ANK_REP_REGION. 1 hit. PS50088. ANK_REPEAT. 9 hits. PS00107. PROTEIN_KINASE_ATP. 1 hit. PS50011. PROTEIN_KINASE_DOM. 1 hit. PS00108. PROTEIN_KINASE_ST. 1 hit. [Graphical view]
ProtoNet	Search...
Other
BindingDB	P57078.
ChEMBL	CHEMBL6083.
ChiTaRS	RIPK4. human.
SOURCE	Search...

Entry information

Entry name

RIPK4_HUMAN

Accession

Primary (citable) accession number: P57078
Secondary accession number(s): Q96KH0

Entry history

Integrated into UniProtKB/Swiss-Prot:	December 1, 2000
Last sequence update:	December 1, 2000
Last modified:	May 1, 2013
This is version 116 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any 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.