dbPTM

RIPK1_HUMAN - PTM Information in dbPTM

Basic Information of Protein

Overview of Protein Modification Sites with Functional and Structural Information
UniProt ID	RIPK1_HUMAN
UniProt AC	Q13546
Protein Name	Receptor-interacting serine/threonine-protein kinase 1
Gene Name	RIPK1
Organism	Homo sapiens (Human).
Sequence Length	671
Subcellular Localization	Cytoplasm. Cell membrane.
Protein Description	Serine-threonine kinase which transduces inflammatory and cell-death signals (programmed necrosis) following death receptors ligation, activation of pathogen recognition receptors (PRRs), and DNA damage. Upon activation of TNFR1 by the TNF-alpha family cytokines, TRADD and TRAF2 are recruited to the receptor. Phosphorylates DAB2IP at 'Ser-728' in a TNF-alpha-dependent manner, and thereby activates the MAP3K5-JNK apoptotic cascade. Ubiquitination by TRAF2 via 'Lys-63'-link chains acts as a critical enhancer of communication with downstream signal transducers in the mitogen-activated protein kinase pathway and the NF-kappa-B pathway, which in turn mediate downstream events including the activation of genes encoding inflammatory molecules. Polyubiquitinated protein binds to IKBKG/NEMO, the regulatory subunit of the IKK complex, a critical event for NF-kappa-B activation. Interaction with other cellular RHIM-containing adapters initiates gene activation and cell death. RIPK1 and RIPK3 association, in particular, forms a necrosis-inducing complex..
Protein Sequence	MQPDMSLNVIKMKSSDFLESAELDSGGFGKVSLCFHRTQGLMIMKTVYKGPNCIEHNEALLEEAKMMNRLRHSRVVKLLGVIIEEGKYSLVMEYMEKGNLMHVLKAEMSTPLSVKGRIILEIIEGMCYLHGKGVIHKDLKPENILVDNDFHIKIADLGLASFKMWSKLNNEEHNELREVDGTAKKNGGTLYYMAPEHLNDVNAKPTEKSDVYSFAVVLWAIFANKEPYENAICEQQLIMCIKSGNRPDVDDITEYCPREIISLMKLCWEANPEARPTFPGIEEKFRPFYLSQLEESVEEDVKSLKKEYSNENAVVKRMQSLQLDCVAVPSSRSNSATEQPGSLHSSQGLGMGPVEESWFAPSLEHPQEENEPSLQSKLQDEANYHLYGSRMDRQTKQQPRQNVAYNREEERRRRVSHDPFAQQRPYENFQNTEGKGTAYSSAASHGNAVHQPSGLTSQPQVLYQNNGLYSSHGFGTRPLDPGTAGPRVWYRPIPSHMPSLHNIPVPETNYLGNTPTMPFSSLPPTDESIKYTIYNSTGIQIGAYNYMEIGGTSSSLLDSTNTNFKEEPAAKYQAIFDNTTSLTDKHLDPIRENLGKHWKNCARKLGFTQSQIDEIDHDYERDGLKEKVYQMLQKWVMREGIKGATVGKLAQALHQCSRIDLLSSLIYVSQN

Experimental Post-Translational Modification Sites

* ASA = Accessible Surface Area

Locations	Modification	Substrate Peptides & Secondary Structure	ASA (%)	Reference
6	Phosphorylation	--MQPDMSLNVIKMK --CCCCCCEEEEEEC	24.95	18408713
11	Ubiquitination	DMSLNVIKMKSSDFL CCCEEEEEECCHHHH	35.67	-
13	Ubiquitination	SLNVIKMKSSDFLES CEEEEEECCHHHHHH	41.63	-
14	Phosphorylation	LNVIKMKSSDFLESA EEEEEECCHHHHHHH	31.47	-
15	Phosphorylation	NVIKMKSSDFLESAE EEEEECCHHHHHHHE	27.19	-
20	Phosphorylation	KSSDFLESAELDSGG CCHHHHHHHEECCCC	29.23	19060867
25	Phosphorylation	LESAELDSGGFGKVS HHHHEECCCCCCEEE	54.14	18408713
32	Phosphorylation	SGGFGKVSLCFHRTQ CCCCCEEEEEEECCC	23.94	-
38	Phosphorylation	VSLCFHRTQGLMIMK EEEEEECCCCEEEEE	20.58	-
49	Ubiquitination	MIMKTVYKGPNCIEH EEEEEEECCCCHHHC	64.65	-
105	Ubiquitination	GNLMHVLKAEMSTPL CCCEEEEEECCCCCC	41.01	-
108	Sulfoxidation	MHVLKAEMSTPLSVK EEEEEECCCCCCCCC	6.89	30846556
115	Ubiquitination	MSTPLSVKGRIILEI CCCCCCCCCHHHHHH	38.81	17883243
137	Ubiquitination	HGKGVIHKDLKPENI CCCCEECCCCCHHHE	54.34	-
140	Ubiquitination	GVIHKDLKPENILVD CEECCCCCHHHEEEC	61.49	-
153	Ubiquitination	VDNDFHIKIADLGLA ECCCCEEEHHHHHHH	24.22	-
161	Phosphorylation	IADLGLASFKMWSKL HHHHHHHHHHHHHHH	30.37	28857561
163	Ubiquitination	DLGLASFKMWSKLNN HHHHHHHHHHHHHCC	36.64	-
166	Phosphorylation	LASFKMWSKLNNEEH HHHHHHHHHHCCHHH	24.62	29440439
167	Ubiquitination	ASFKMWSKLNNEEHN HHHHHHHHHCCHHHH	39.46	-
184	Ubiquitination	REVDGTAKKNGGTLY HCCCCCEEECCCEEE	46.76	-
185	Ubiquitination	EVDGTAKKNGGTLYY CCCCCEEECCCEEEE	59.36	-
262	Phosphorylation	YCPREIISLMKLCWE HCHHHHHHHHHHHHH	28.24	-
284	Ubiquitination	TFPGIEEKFRPFYLS CCCCHHHHCCHHHHH	33.61	-
291	Phosphorylation	KFRPFYLSQLEESVE HCCHHHHHHHHHHHH	22.72	28450419
296	Phosphorylation	YLSQLEESVEEDVKS HHHHHHHHHHHHHHH	26.00	28450419
302	Ubiquitination	ESVEEDVKSLKKEYS HHHHHHHHHHHHHHC	63.49	-
303	Phosphorylation	SVEEDVKSLKKEYSN HHHHHHHHHHHHHCC	45.32	18408713
306	Ubiquitination	EDVKSLKKEYSNENA HHHHHHHHHHCCHHH	68.15	-
308	Phosphorylation	VKSLKKEYSNENAVV HHHHHHHHCCHHHHH	26.19	27642862
309	Phosphorylation	KSLKKEYSNENAVVK HHHHHHHCCHHHHHH	38.47	28857561
316	Ubiquitination	SNENAVVKRMQSLQL CCHHHHHHHHHHHCC	35.24	21906983
316	Acetylation	SNENAVVKRMQSLQL CCHHHHHHHHHHHCC	35.24	25953088
320	Phosphorylation	AVVKRMQSLQLDCVA HHHHHHHHHCCEEEE	14.56	29255136
330	O-linked_Glycosylation	LDCVAVPSSRSNSAT CEEEECCCCCCCCCC	31.61	30059200
330	Phosphorylation	LDCVAVPSSRSNSAT CEEEECCCCCCCCCC	31.61	25159151
331	Phosphorylation	DCVAVPSSRSNSATE EEEECCCCCCCCCCC	33.39	25159151
331	O-linked_Glycosylation	DCVAVPSSRSNSATE EEEECCCCCCCCCCC	33.39	30059200
333	Phosphorylation	VAVPSSRSNSATEQP EECCCCCCCCCCCCC	36.76	18408713
335	Phosphorylation	VPSSRSNSATEQPGS CCCCCCCCCCCCCCC	37.50	28464451
337	Phosphorylation	SSRSNSATEQPGSLH CCCCCCCCCCCCCCC	34.67	18669648
342	Phosphorylation	SATEQPGSLHSSQGL CCCCCCCCCCCCCCC	29.59	26552605
345	Phosphorylation	EQPGSLHSSQGLGMG CCCCCCCCCCCCCCC	29.65	26552605
346	Phosphorylation	QPGSLHSSQGLGMGP CCCCCCCCCCCCCCC	19.95	18669648
357	Phosphorylation	GMGPVEESWFAPSLE CCCCCCHHCCCCCCC	17.62	27251275
377	Ubiquitination	NEPSLQSKLQDEANY CCCCHHHHHHHHHHH	36.89	16543241
384	Phosphorylation	KLQDEANYHLYGSRM HHHHHHHHHHHHHHC	10.55	21945579
387	Phosphorylation	DEANYHLYGSRMDRQ HHHHHHHHHHHCCCC	10.35	21945579
389	Phosphorylation	ANYHLYGSRMDRQTK HHHHHHHHHCCCCCC	15.75	21945579
405	Phosphorylation	QPRQNVAYNREEERR CCCCCCCCCHHHHHH	15.52	20068231
416	Phosphorylation	EERRRRVSHDPFAQQ HHHHHHHCCCHHHHC	21.99	21945579
426	Phosphorylation	PFAQQRPYENFQNTE HHHHCCCCCCCCCCC	26.20	21945579
432	Phosphorylation	PYENFQNTEGKGTAY CCCCCCCCCCCCCCC	35.02	21945579
463	Phosphorylation	TSQPQVLYQNNGLYS CCCCEEEECCCCCCC	15.44	-
469	Phosphorylation	LYQNNGLYSSHGFGT EECCCCCCCCCCCCC	14.99	-
470	Phosphorylation	YQNNGLYSSHGFGTR ECCCCCCCCCCCCCC	22.39	-
471	Phosphorylation	QNNGLYSSHGFGTRP CCCCCCCCCCCCCCC	17.67	-
477	Methylation	SSHGFGTRPLDPGTA CCCCCCCCCCCCCCC	30.11	115386377
483	Phosphorylation	TRPLDPGTAGPRVWY CCCCCCCCCCCCEEE	33.55	-
487	Methylation	DPGTAGPRVWYRPIP CCCCCCCCEEEEECC	30.59	115386381
490	Phosphorylation	TAGPRVWYRPIPSHM CCCCCEEEEECCCCC	12.03	-
530	Acetylation	PPTDESIKYTIYNST CCCCCCCEEEEECCC	45.69	23201684
571	Ubiquitination	FKEEPAAKYQAIFDN CCCCHHHHHHHHHCC	39.75	17883243
585	Ubiquitination	NTTSLTDKHLDPIRE CCCCCCHHCCHHHHH	40.61	-
596	Malonylation	PIRENLGKHWKNCAR HHHHHHHHHHHHHHH	49.84	32601280
596	Ubiquitination	PIRENLGKHWKNCAR HHHHHHHHHHHHHHH	49.84	-
604	Malonylation	HWKNCARKLGFTQSQ HHHHHHHHHCCCHHH	34.14	26320211
604	Acetylation	HWKNCARKLGFTQSQ HHHHHHHHHCCCHHH	34.14	26051181
604	Ubiquitination	HWKNCARKLGFTQSQ HHHHHHHHHCCCHHH	34.14	-
608	Phosphorylation	CARKLGFTQSQIDEI HHHHHCCCHHHHHHC	26.05	28857561
610	Phosphorylation	RKLGFTQSQIDEIDH HHHCCCHHHHHHCCC	26.50	26657352
619	Phosphorylation	IDEIDHDYERDGLKE HHHCCCCHHHCCHHH	14.94	27642862
625	Ubiquitination	DYERDGLKEKVYQML CHHHCCHHHHHHHHH	62.10	-
627	Ubiquitination	ERDGLKEKVYQMLQK HHCCHHHHHHHHHHH	44.66	1788324
642	Ubiquitination	WVMREGIKGATVGKL HHHHCCCCCCHHHHH	54.04	-
642	Acetylation	WVMREGIKGATVGKL HHHHCCCCCCHHHHH	54.04	7374181
648	Acetylation	IKGATVGKLAQALHQ CCCCHHHHHHHHHHH	35.99	7374193
664	Phosphorylation	SRIDLLSSLIYVSQN CHHHHHHHHHHHCCC	20.82	24719451

Upstream regulatory proteins (kinases for phosphorylation sites, E3 ubiquitin ligases of ubiquitination sites, ...)

Modified Location	Modified Residue	Modification	Type of Upstream Proteins	Gene Name of Upstream Proteins	UniProt AC of Upstream Proteins	Sources
6	S	Phosphorylation	Kinase	IKKB	O14920	Uniprot
6	S	Phosphorylation	Kinase	IKKA	O15111	Uniprot
14	S	Phosphorylation	Kinase	RIPK1	Q13546	PSP
15	S	Phosphorylation	Kinase	RIPK1	Q13546	PSP
20	S	Phosphorylation	Kinase	RIPK1	Q13546	PSP
25	S	Phosphorylation	Kinase	IKKA	O15111	Uniprot
25	S	Phosphorylation	Kinase	IKKB	O14920	Uniprot
161	S	Phosphorylation	Kinase	RIPK1	Q13546	PSP
161	S	Phosphorylation	Kinase	RIPK3	Q9Y572	Uniprot
166	S	Phosphorylation	Kinase	RIPK1	Q13546	PSP
262	S	Phosphorylation	Kinase	ULK1	O75385	PSP
291	S	Phosphorylation	Kinase	ULK1	O75385	PSP
296	S	Phosphorylation	Kinase	ULK1	O75385	PSP
320	S	Phosphorylation	Kinase	MAPKAPK2	P49137	PSP
320	S	Phosphorylation	Kinase	MAP3K7	O43318	Uniprot
320	S	Phosphorylation	Kinase	ULK1	O75385	PSP
331	S	Phosphorylation	Kinase	MAP3K7	O43318	Uniprot
333	S	Phosphorylation	Kinase	MAP3K7	O43318	Uniprot
333	S	Phosphorylation	Kinase	ULK1	O75385	PSP
335	S	Phosphorylation	Kinase	ULK1	O75385	PSP
337	T	Phosphorylation	Kinase	ULK1	O75385	PSP
345	S	Phosphorylation	Kinase	ULK1	O75385	PSP
346	S	Phosphorylation	Kinase	ULK1	O75385	PSP
357	S	Phosphorylation	Kinase	ULK1	O75385	PSP
389	S	Phosphorylation	Kinase	ULK1	O75385	PSP
-	K	Ubiquitination	E3 ubiquitin ligase	RFFL	Q8WZ73	PMID:18450452
-	K	Ubiquitination	E3 ubiquitin ligase	PELI1	Q96FA3	PMID:19734906
-	K	Ubiquitination	E3 ubiquitin ligase	TNFAIP3	P21580	PMID:15258597
-	K	Ubiquitination	E3 ubiquitin ligase	BIRC2	Q13490	PMID:18570872
-	K	Ubiquitination	E3 ubiquitin ligase	BIRC3	Q13489	PMID:18570872
-	K	Ubiquitination	E3 ubiquitin ligase	TANK	Q92844	PMID:22199232
-	K	Ubiquitination	E3 ubiquitin ligase	RNF216	Q9NWF9	PMID:16968706
-	K	Ubiquitination	E3 ubiquitin ligase	RNF31	Q96EP0	PMID:22199232
-	K	Ubiquitination	E3 ubiquitin ligase	ITCH	Q96J02	PMID:22199232
-	K	Ubiquitination	E3 ubiquitin ligase	RNF34	Q969K3	PMID:22199232
-	K	Ubiquitination	E3 ubiquitin ligase	RBCK1	Q9BYM8	PMID:22199232
-	K	Ubiquitination	E3 ubiquitin ligase	TRAF2	Q12933	PMID:18641654

Functions of PTM Sites

Modified Location	Modified Residue	Modification	Reference
11	K	ubiquitylation	21455173
Ubiquitinated with 'Lys-11'-, 'Lys-48'-, 'Lys-63'- and linear-linked type ubiquitin.33).
25	S	Phosphorylation	18408713
Phosphorylation at Ser-25 represses its kinase activity and consequently prevents TNF-mediated RIPK1-dependent cell death.
48	K	ubiquitylation	21931591
Polyubiquitinated with 'Lys-48' and 'Lys-63'-linked chains by BIRC2/c-IAP1 and BIRC3/c-IAP2, leading to activation of NF-kappa-B.
48	K	ubiquitylation	21455173
Ubiquitinated with 'Lys-11'-, 'Lys-48'-, 'Lys-63'- and linear-linked type ubiquitin.33).
63	K	ubiquitylation	21455173
Ubiquitinated with 'Lys-11'-, 'Lys-48'-, 'Lys-63'- and linear-linked type ubiquitin.33).
161	S	Phosphorylation	18408713
Phosphorylation of Ser-161 by RIPK3 is necessary for the formation of the necroptosis-inducing complex.
320	S	Phosphorylation	18408713
Phosphorylated at Ser-320 by MAP3K7 which requires prior ubiquitination with 'Lys-63'-linked chains by BIRC2/c-IAP1 and BIRC3/c-IAP2 (By similarity).
320	S	Phosphorylation	18408713
Ubiquitination at Lys-377 with 'Lys-63'-linked chains by BIRC2/c-IAP1 and BIRC3/c-IAP2 is essential for its phosphorylation at Ser-320 mediated by MAP3K7 (By similarity).
320	S	ubiquitylation	18408713
Phosphorylated at Ser-320 by MAP3K7 which requires prior ubiquitination with 'Lys-63'-linked chains by BIRC2/c-IAP1 and BIRC3/c-IAP2 (By similarity).
320	S	ubiquitylation	18408713
Ubiquitination at Lys-377 with 'Lys-63'-linked chains by BIRC2/c-IAP1 and BIRC3/c-IAP2 is essential for its phosphorylation at Ser-320 mediated by MAP3K7 (By similarity).
377	K	Phosphorylation	16603398
Ubiquitination at Lys-377 with 'Lys-63'-linked chains by BIRC2/c-IAP1 and BIRC3/c-IAP2 is essential for its phosphorylation at Ser-320 mediated by MAP3K7 (By similarity).
377	K	ubiquitylation	16603398
Ubiquitination at Lys-377 with 'Lys-63'-linked chains by BIRC2/c-IAP1 and BIRC3/c-IAP2 is essential for its phosphorylation at Ser-320 mediated by MAP3K7 (By similarity).

Disease-associated PTM Sites based on SAP

* Distance = the distance between SAP position and PTM sites.

Modified Location	Modification	Variant Position (Distance <= 10)	Residue Change	SAP	Related Disease	Reference
Oops, there are no SNP-PTM records of RIPK1_HUMAN !!

Protein-Protein Interaction

Interacting Protein	Gene Name	Interaction Type	PPI Reference
TCAM1_HUMAN	TICAM1	physical	15064760
CRADD_HUMAN	CRADD	physical	9044836
FADD_HUMAN	FADD	physical	11854271
RN216_HUMAN	RNF216	physical	11854271
TNR1A_HUMAN	TNFRSF1A	physical	11002422
NEMO_HUMAN	IKBKG	physical	10880512
TRAF5_HUMAN	TRAF5	physical	11479302
SQSTM_HUMAN	SQSTM1	physical	10356400
TRADD_HUMAN	TRADD	physical	8612133
TRAF2_HUMAN	TRAF2	physical	8612133
TRAF2_HUMAN	TRAF2	physical	9020361
TNAP3_HUMAN	TNFAIP3	physical	19131965
RNF11_HUMAN	RNF11	physical	19131965
TAXB1_HUMAN	TAX1BP1	physical	19131965
BIRC2_HUMAN	BIRC2	physical	18570872
BIRC3_HUMAN	BIRC3	physical	18570872
M3K7_HUMAN	MAP3K7	physical	18570872
TAB2_HUMAN	TAB2	physical	18299187
CYLD_HUMAN	CYLD	physical	17981138
RN216_HUMAN	RNF216	physical	16968706
HS90A_HUMAN	HSP90AA1	physical	16968706
M3K7_HUMAN	MAP3K7	physical	16543241
NEMO_HUMAN	IKBKG	physical	16543241
MRCKB_HUMAN	CDC42BPB	physical	20936779
UBP21_HUMAN	USP21	physical	19910467
TRAF2_HUMAN	TRAF2	physical	21282461
PELI1_HUMAN	PELI1	physical	19734906
TCAM1_HUMAN	TICAM1	physical	19734906
BIRC2_HUMAN	BIRC2	physical	21113135
FADD_HUMAN	FADD	physical	21737329
CASP8_HUMAN	CASP8	physical	21737329
UBP2_HUMAN	USP2	physical	22179575
TAXB1_HUMAN	TAX1BP1	physical	18246070
TNAP3_HUMAN	TNFAIP3	physical	18246070
CASP8_HUMAN	CASP8	physical	19373245
FADD_HUMAN	FADD	physical	19373245
NEMO_HUMAN	IKBKG	physical	21606198
M3K7_HUMAN	MAP3K7	physical	21606198
IKKB_HUMAN	IKBKB	physical	21606198
TAB2_HUMAN	TAB2	physical	15327770
CLIP3_HUMAN	CLIP3	physical	22297296
DAB2P_HUMAN	DAB2IP	physical	17389591
DAB2P_HUMAN	DAB2IP	physical	15310755
NEMO_HUMAN	IKBKG	physical	11262391
RIPK1_HUMAN	RIPK1	physical	15001576
ANXA1_HUMAN	ANXA1	physical	21383699
IKKB_HUMAN	IKBKB	physical	10980203
FADD_HUMAN	FADD	physical	21458669
UBP4_HUMAN	USP4	physical	23313255
M3K8_HUMAN	MAP3K8	physical	16291755
TRAF2_HUMAN	TRAF2	physical	24434549
M3K7_HUMAN	MAP3K7	physical	24434549
CASP8_HUMAN	CASP8	physical	24577083
FADD_HUMAN	FADD	physical	24577083
RFFL_HUMAN	RFFL	physical	18450452
RIPK1_HUMAN	RIPK1	physical	25416956
UBC_HUMAN	UBC	physical	25715336
UBC_HUMAN	UBC	physical	26017671
EGLN3_HUMAN	EGLN3	physical	26612615
BIRC2_HUMAN	BIRC2	physical	26612615
TRAF2_HUMAN	TRAF2	physical	25882049
ERN1_HUMAN	ERN1	physical	25476903
FADD_HUMAN	FADD	physical	26972597
CFLAR_HUMAN	CFLAR	physical	26972597
CASP8_HUMAN	CASP8	physical	26972597
RIPK1_HUMAN	RIPK1	physical	27045108
CASP8_HUMAN	CASP8	physical	26733177
FADD_HUMAN	FADD	physical	26733177
XAF1_HUMAN	XAF1	physical	27768232
TRAF2_HUMAN	TRAF2	physical	27768232
TRADD_HUMAN	TRADD	physical	27768232
CYLD_HUMAN	CYLD	physical	28900035

Drug and Disease Associations

Kegg Disease
There are no disease associations of PTM sites.
OMIM Disease
There are no disease associations of PTM sites.
Kegg Drug
There are no disease associations of PTM sites.
DrugBank
There are no disease associations of PTM sites.

Regulatory Network of RIPK1_HUMAN

Related Literatures of Post-Translational Modification

Phosphorylation
Reference	PubMed
"Identification of RIP1 kinase as a specific cellular target ofnecrostatins."; Degterev A., Hitomi J., Germscheid M., Ch'en I.L., Korkina O.,Teng X., Abbott D., Cuny G.D., Yuan C., Wagner G., Hedrick S.M.,Gerber S.A., Lugovskoy A., Yuan J.; Nat. Chem. Biol. 4:313-321(2008). Cited for: MUTAGENESIS OF SER-161, INHIBITION BY NECROSTATIN-1, ANDPHOSPHORYLATION AT SER-6; SER-20; SER-25; SER-161; SER-166; SER-303;SER-320 AND SER-333.	18408713 [Abstract]
"A quantitative atlas of mitotic phosphorylation."; Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,Elledge S.J., Gygi S.P.; Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008). Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-320, AND MASSSPECTROMETRY.	18669648 [Abstract]
"Robust phosphoproteomic profiling of tyrosine phosphorylation sitesfrom human T cells using immobilized metal affinity chromatography andtandem mass spectrometry."; Brill L.M., Salomon A.R., Ficarro S.B., Mukherji M., Stettler-Gill M.,Peters E.C.; Anal. Chem. 76:2763-2772(2004). Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT TYR-384; TYR-387 ANDSER-389, AND MASS SPECTROMETRY.	15144186 [Abstract]

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