RIPK1

Functionⁱ

Serine-threonine kinase which is a key regulator of TNF-mediated apoptosis, necroptosis and inflammatory pathways (PubMed:25459879, PubMed:31827281, PubMed:31827280). Exhibits kinase activity-dependent functions that trigger cell death and kinase-independent scaffold functions regulating inflammatory signaling and cell survival (PubMed:11101870, PubMed:25459879). Initiates ripoptocide which describes cell death that is dependent on RIPK1, be it apoptosis or necroptosis (PubMed:31457011). Upon binding of TNF to TNFR1, RIPK1 is recruited to the TNF-R1 signaling complex (TNF-RSC also known as complex I) where it acts as a scaffold protein promoting cell survival, in part, by activating the canonical NF-kB pathway (By similarity). Specific conditions can however activate RIPK1, and its kinase activity then regulates assembly of two death-inducing complexes, namely complex IIa (RIPK1-FADD-CASP8) and the complex IIb (RIPK1-RIPK3-MLKL) and these complexes respectively drive apoptosis or necroptosis, a regulated form of necrosis (PubMed:19524513, PubMed:19524512, PubMed:29440439, PubMed:30988283). Also involved in inflammatory response by promoting transcriptional production of pro-inflammatory cytokines, such as interleukin-6 (IL6) (PubMed:31827281, PubMed:31827280). During embryonic development suppresses apoptosis and necroptosis and prevents the interaction of TRADD with FADD thereby limiting aberrant activation of CASP8 (By similarity). Phosphorylates DAB2IP at 'Ser-728' in a TNF-alpha-dependent manner, and thereby activates the MAP3K5-JNK apoptotic cascade (PubMed:17389591). Required for ZBP1-induced NF-kappa-B activation and activation of NF-kappa-B by DNA damage and IR (By similarity).2 PublicationsBy similarity8 Publications

Catalytic activityⁱ

Activity regulationⁱ

Serine-threonine kinase activity is inhibited by linear polyubiquitination ('Met-1'-linked) by the LUBAC complex (By similarity). Inhibited by necrostatins, including necrostatin-1, necrostatin-3 and necrostatin-4 (PubMed:23473668).By similarity1 Publication

Sites

Feature key	Position(s)	DescriptionActions	Graphical view	Length
Binding siteⁱ	45	ATPPROSITE-ProRule annotation		1
Active siteⁱ	138	Proton acceptorPROSITE-ProRule annotation		1

Regions

Feature key	Position(s)	DescriptionActions	Graphical view	Length
Nucleotide bindingⁱ	23 – 31	ATPPROSITE-ProRule annotation		9

GO - Molecular functionⁱ

Complete GO annotation on QuickGO ...

GO - Biological processⁱ

Complete GO annotation on QuickGO ...

Keywordsⁱ

Molecular function	Kinase, Serine/threonine-protein kinase, Transferase
Biological process	Apoptosis, Host-virus interaction, Inflammatory response, Necrosis
Ligand	ATP-binding, Nucleotide-binding

Enzyme and pathway databases

BRENDAⁱ	2.7.10.2 2681
Reactomeⁱ	R-HSA-140534 Caspase activation via Death Receptors in the presence of ligand R-HSA-168927 TICAM1, RIP1-mediated IKK complex recruitment R-HSA-1810476 RIP-mediated NFkB activation via ZBP1 R-HSA-2562578 TRIF-mediated programmed cell death R-HSA-3295583 TRP channels R-HSA-3371378 Regulation by c-FLIP R-HSA-5213460 RIPK1-mediated regulated necrosis R-HSA-5218900 CASP8 activity is inhibited R-HSA-5357786 TNFR1-induced proapoptotic signaling R-HSA-5357905 Regulation of TNFR1 signaling R-HSA-5357956 TNFR1-induced NFkappaB signaling pathway R-HSA-5675482 Regulation of necroptotic cell death R-HSA-5689880 Ub-specific processing proteases R-HSA-5689896 Ovarian tumor domain proteases R-HSA-69416 Dimerization of procaspase-8 R-HSA-75893 TNF signaling R-HSA-9013957 TLR3-mediated TICAM1-dependent programmed cell death R-HSA-933543 NF-kB activation through FADD/RIP-1 pathway mediated by caspase-8 and -10 R-HSA-937041 IKK complex recruitment mediated by RIP1
SignaLinkⁱ	Q13546
SIGNORⁱ	Q13546

Names & Taxonomyⁱ

Protein namesⁱ	Recommended name: Receptor-interacting serine/threonine-protein kinase 1 (EC:2.7.11.14 Publications) Alternative name(s): Cell death protein RIP1 Publication Receptor-interacting protein 11 Publication Short name: RIP-11 Publication
Gene namesⁱ	Name:RIPK1Imported Synonyms:RIP1 Publication, RIP11 Publication
Organismⁱ	Homo sapiens (Human)
Taxonomic identifierⁱ	9606 [NCBI]
Taxonomic lineageⁱ	cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Dipnotetrapodomorpha › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Boreoeutheria › Euarchontoglires › Primates › Haplorrhini › Simiiformes › Catarrhini › Hominoidea › Hominidae › Homininae › Homo
Proteomesⁱ	UP000005640 Componentⁱ: Chromosome 6

Organism-specific databases

EuPathDBⁱ	HostDB:ENSG00000137275.13
Human Gene Nomenclature Database More...HGNCⁱ	HGNC:10019 RIPK1
MIMⁱ	603453 gene
neXtProtⁱ	NX_Q13546

Keywords - Cellular componentⁱ

Cell membrane, Cytoplasm, Membrane

Pathology & Biotechⁱ

Involvement in diseaseⁱ

Immunodeficiency 57 (IMD57)1 Publication

The disease is caused by mutations affecting the gene represented in this entry. RIPK1-deficient immune cells from IMD57 patients have impaired proinflammatory signaling leading to dysregulated cytokine secretion and are prone to necroptosis.1 Publication

Disease descriptionAn autosomal recessive primary immunodeficiency characterized by lymphopenia and recurrent viral, bacterial, and fungal infections. Patients exhibit early-onset inflammatory bowel disease involving the upper and lower gastrointestinal tract, and develop progressive polyarthritis.

Related information in OMIM

Defects in RIPK1 are the cause of cleavage-resistant RIPK1-induced autoinflammatory syndrome (CRIA), an autosomal dominant syndrome characterized by fevers and pronounced lymphadenopathy beginning in early childhood and continuing throughout adulthood (PubMed:31827281, PubMed:31827280). Patients experience fevers occurring approximately every 2-4 weeks, lasting 1-7 days, and reaching temperatures as high as 40-41 degrees Celsius (PubMed:31827281, PubMed:31827280). In contrast to more severe autoinflammatory disorders, no signs of rash, arthritis, genital ulcers or end-stage organ damage are observed, and the conditions are not threatening life of the patients (PubMed:31827281, PubMed:31827280). The disease is caused by mutations affecting the gene represented in this entry (PubMed:31827281, PubMed:31827280). Defects are caused by strong RIPK1-dependent activation of inflammatory signaling pathways and overproduction of inflammatory cytokines and chemokines, such as interleukin-6 (IL6) and TNF (PubMed:31827281, PubMed:31827280).2 Publications

Mutagenesis

Feature key	Position(s)	DescriptionActions	Length
Mutagenesisⁱ	25	S → D: Phophomimetic mutant. Significant loss of kinase activity. 1 Publication	1
Mutagenesisⁱ	45	K → A: Abolishes kinase activity. 2 Publications	1
Mutagenesisⁱ	161	S → A: Decreases RIPK1 kinase activity. 1 Publication	1
Mutagenesisⁱ	161	S → E: No effect on RIPK1 autophosphorylation. 1 Publication	1
Mutagenesisⁱ	324	D → K: Abolishes cleavage by caspase-8. 1 Publication	1
Mutagenesisⁱ	377	K → R: Abolishes RIP-mediated NF-Kappa-B activation. 1 Publication	1
Mutagenesisⁱ	599	K → R: Blocks homodimerization, necroptosis and apoptosis. 1 Publication	1

Organism-specific databases

DisGeNET More...DisGeNETⁱ	8737
MalaCards human disease database More...MalaCardsⁱ	RIPK1
MIMⁱ	618108 phenotype
Open Targets More...OpenTargetsⁱ	ENSG00000137275
PharmGKBⁱ	PA34394

Miscellaneous databases

Pharosⁱ	Q13546 Tchem

Pharosⁱ

Q13546 Tchem

Chemistry databases

ChEMBLⁱ	CHEMBL5464
Drug and drug target database More...DrugBankⁱ	DB12010 Fostamatinib
DrugCentral More...DrugCentralⁱ	Q13546
IUPHAR/BPS Guide to PHARMACOLOGY More...GuidetoPHARMACOLOGYⁱ	2189

Polymorphism and mutation databases

BioMutaⁱ	RIPK1
DMDMⁱ	60393639

PTM / Processingⁱ

Molecule processing

Feature key	Position(s)	DescriptionActions	Graphical view	Length
ChainⁱPRO_0000086606	1 – 671	Receptor-interacting serine/threonine-protein kinase 1Add BLAST		671

Amino acid modifications

Feature key	Position(s)	DescriptionActions	Length
Modified residueⁱ	6	Phosphoserine; by IKKA and IKKB1 Publication	1
Modified residueⁱ	20	Phosphoserine; by autocatalysisSequence analysis	1
Modified residueⁱ	25	Phosphoserine; by IKKA and IKKB2 Publications	1
Modified residueⁱ	161	Phosphoserine; by RIPK3 and autocatalysisSequence analysis	1
Modified residueⁱ	166	Phosphoserine; by autocatalysisSequence analysis2 Publications	1
Modified residueⁱ	303	Phosphoserine1 Publication	1
Modified residueⁱ	320	Phosphoserine; by MAP3K7Combined sources1 Publication	1
Modified residueⁱ	331	Phosphoserine; by MAP3K7By similarity	1
Modified residueⁱ	333	Phosphoserine; by MAP3K71 Publication	1
Cross-linkⁱ	377	Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin)1 Publication
Modified residueⁱ	384	PhosphotyrosineCombined sources	1

Post-translational modificationⁱ

Proteolytically cleaved by CASP8 at Asp-324 (PubMed:10521396, PubMed:31827281, PubMed:31827280). Cleavage is crucial for limiting TNF-induced apoptosis, necroptosis and inflammatory response (PubMed:31827281, PubMed:31827280). Cleavage abolishes NF-kappa-B activation and enhances the interaction of TRADD with FADD (PubMed:10521396).By similarity3 Publications

RIPK1 and RIPK3 undergo reciprocal auto- and trans-phosphorylation (PubMed:18408713, PubMed:19524513, PubMed:31827280). Phosphorylation of Ser-161 by RIPK3 is necessary for the formation of the necroptosis-inducing complex (PubMed:18408713). Phosphorylation at Ser-25 represses its kinase activity and consequently prevents TNF-mediated RIPK1-dependent cell death (PubMed:30988283). 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). This phosphorylation positively regulates RIPK1 interaction with RIPK3 to promote necroptosis but negatively regulates RIPK1 kinase activity and its interaction with FADD to mediate apoptosis (By similarity).By similarity4 Publications

Ubiquitinated with 'Lys-11'-, 'Lys-48'-, 'Lys-63'- and linear-linked type ubiquitin (PubMed:15258597, PubMed:16603398, PubMed:18450452, PubMed:21455173, PubMed:21931591, PubMed:29883609, Ref. 33). Polyubiquitination with 'Lys-63'-linked chains by TRAF2 induces association with the IKK complex (PubMed:15258597). Deubiquitination of 'Lys-63'-linked chains and polyubiquitination with 'Lys-48'-linked chains by TNFAIP3 leads to RIPK1 proteasomal degradation and consequently down-regulates TNF-alpha-induced NFkappa-B signaling (PubMed:15258597). 'Lys-48'-linked polyubiquitination by RFFL or RNF34 also promotes proteasomal degradation and negatively regulates TNF-alpha-induced NF-kappa-B signaling (PubMed:18450452, Ref. 33). Linear polyubiquitinated; the head-to-tail linear polyubiquitination ('Met-1'-linked) is mediated by the LUBAC complex and decreases protein kinase activity (PubMed:21455173). Deubiquitination of linear polyubiquitin by CYLD promotes the kinase activity (By similarity). Polyubiquitinated with 'Lys-48' and 'Lys-63'-linked chains by BIRC2/c-IAP1 and BIRC3/c-IAP2, leading to activation of NF-kappa-B (PubMed:21931591). Ubiquitinated with 'Lys-63'-linked chains by PELI1 (PubMed:29883609). 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). This ubiquitination is required for NF-kB activation, suppresses RIPK1 kinase activity and plays a critical role in preventing cell death during embryonic development (By similarity).By similarity7 Publications

Sites

Feature key	Position(s)	DescriptionActions	Graphical view	Length
Siteⁱ	324 – 325	Cleavage; by CASP83 Publications		2

Keywords - PTMⁱ

Isopeptide bond, Phosphoprotein, Ubl conjugation

Proteomic databases

The CPTAC Assay portal More...CPTACⁱ	CPTAC-1053 CPTAC-900 CPTAC-901 CPTAC-902
EPDⁱ	Q13546
jPOSTⁱ	Q13546
MassIVEⁱ	Q13546
MaxQB - The MaxQuant DataBase More...MaxQBⁱ	Q13546
PaxDbⁱ	Q13546
PeptideAtlas More...PeptideAtlasⁱ	Q13546
PRIDEⁱ	Q13546
ProteomicsDBⁱ	59527 [Q13546-1] 59528 [Q13546-2]

PTM databases

iPTMnetⁱ	Q13546
MetOSiteⁱ	Q13546
PhosphoSitePlusⁱ	Q13546

Expressionⁱ

Gene expression databases

Bgeeⁱ	ENSG00000137275 Expressed in right lobe of liver and 183 other tissues
ExpressionAtlasⁱ	Q13546 baseline and differential
Genevisibleⁱ	Q13546 HS

Organism-specific databases

Human Protein Atlas More...HPAⁱ	ENSG00000137275 Low tissue specificity

HPAⁱ

ENSG00000137275 Low tissue specificity

Interactionⁱ

Subunit structureⁱ

Homodimer (PubMed:29440439).

Interacts (via RIP homotypic interaction motif) with RIPK3 (via RIP homotypic interaction motif); this interaction induces RIPK1 phosphorylation and formation of a RIPK1-RIPK3 necroptosis-inducing complex (PubMed:11734559, PubMed:29883609, PubMed:19524512, PubMed:10358032). Upon TNF-induced necrosis, the RIPK1-RIPK3 dimer further interacts with PGAM5 and MLKL; the formation of this complex leads to PGAM5 phosphorylation and increase in PGAM5 phosphatase activity (PubMed:22265414).

Interacts (via the death domain) with TNFRSF6 (via the death domain) and TRADD (via the death domain) (PubMed:8612133). Is recruited by TRADD to TNFRSF1A in a TNF-dependent process (PubMed:24130170). Binds RNF216, EGFR, IKBKG, TRAF1, TRAF2 and TRAF3 (PubMed:8612133, PubMed:9927690, PubMed:11854271, PubMed:11116146).

Interacts with BNLF1 (PubMed:10409763).

Interacts with SQSTM1 upon TNF-alpha stimulation (PubMed:10356400). May interact with MAVS/IPS1 (PubMed:16127453).

Interacts with ZFAND5 (PubMed:14754897).

Interacts with RBCK1 (PubMed:17449468).

Interacts with ZBP1 (By similarity).

Interacts with BIRC2/c-IAP1, BIRC3/c-IAP2 and XIAP/BIRC4 (PubMed:21931591).

Interacts (via kinase domain) with DAB2IP (via Ras-GAP domain); the interaction occurs in a TNF-alpha-dependent manner (PubMed:17389591).

Interacts with ARHGEF2 (PubMed:21887730).

Interacts (via protein kinase domain) with RFFL; involved in RIPK1 ubiquitination (PubMed:18450452).

Interacts with RNF34; involved in RIPK1 ubiquitination (Ref. 33).

Interacts with TICAM1 and this interaction is enhanced in the presence of WDFY1 (PubMed:25736436).

Interacts with PELI1 (PubMed:29883609).

Interacts (via death domain) with CRADD (via death domain); the interaction is direct (PubMed:9044836).

Component of complex IIa composed of at least RIPK1, FADD and CASP8 (By similarity).

Interacts with MAP3K7, CFLAR, CASP8, FADD and NEMO (By similarity).

By similarity23 Publications

(Microbial infection) Interacts with mumps virus protein SH; this interaction inhibits downstream NF-kappa-B pathway activation.

1 Publication

(Microbial infection) Interacts with Murid herpesvirus 1 protein RIR1.

1 Publication

Binary interactionsⁱ

Hide details

Q13546

With	#Exp.	IntAct
ANXA1 [P04083]	5	EBI-358507,EBI-354007
BIRC2 [Q13490]	5	EBI-358507,EBI-514538
BIRC3 [Q13489]	3	EBI-358507,EBI-517709
CASP10 [Q92851]	2	EBI-358507,EBI-495095
CASP8 [Q14790]	27	EBI-358507,EBI-78060
CCDC50 [Q8IVM0]	2	EBI-358507,EBI-723996
CSNK1A1 [P48729]	5	EBI-358507,EBI-1383726
FADD [Q13158]	10	EBI-358507,EBI-494804
IKBKG [Q9Y6K9]	8	EBI-358507,EBI-81279
PYCARD [Q9ULZ3]	2	EBI-358507,EBI-751215
itself	10	EBI-358507,EBI-358507
RIPK3 [Q9Y572]	26	EBI-358507,EBI-298250
TNFRSF1A [P19438]	6	EBI-358507,EBI-299451
TRAF1 [Q13077]	6	EBI-358507,EBI-359224
TRAF2 [Q12933]	8	EBI-358507,EBI-355744
TRAF3 [Q13114]	3	EBI-358507,EBI-357631
USP4 [Q13107]	4	EBI-358507,EBI-723290
E2348C_3231 [B7UI21] from Escherichia coli O127:H6 (strain E2348/69 / EPEC).	4	EBI-358507,EBI-16070376
UL39 [U5TQE9] from Human herpesvirus 1.	3	EBI-358507,EBI-11894787

GO - Molecular functionⁱ

Complete GO annotation on QuickGO ...

Protein-protein interaction databases

BioGRIDⁱ	114274, 101 interactors
ComplexPortalⁱ	CPX-1907 Ripoptosome
CORUMⁱ	Q13546
Database of interacting proteins More...DIPⁱ	DIP-433N
IntActⁱ	Q13546, 75 interactors
Molecular INTeraction database More...MINTⁱ	Q13546
STRINGⁱ	9606.ENSP00000259808

Chemistry databases

BindingDBⁱ

Q13546

Miscellaneous databases

RNActⁱ	Q13546 protein

RNActⁱ

Q13546 protein

Structureⁱ

Secondary structure

Legend: HelixTurnBeta strandPDB Structure known for this area

Feature key	Position(s)	DescriptionActions	Length
Beta strandⁱ	10 – 12	Combined sources	3
Helixⁱ	14 – 16	Combined sources	3
Beta strandⁱ	17 – 19	Combined sources	3
Beta strandⁱ	20 – 22	Combined sources	3
Helixⁱ	25 – 28	Combined sources	4
Beta strandⁱ	30 – 36	Combined sources	7
Turnⁱ	37 – 39	Combined sources	3
Beta strandⁱ	40 – 51	Combined sources	12
Helixⁱ	54 – 56	Combined sources	3
Helixⁱ	57 – 68	Combined sources	12
Beta strandⁱ	78 – 84	Combined sources	7
Beta strandⁱ	87 – 93	Combined sources	7
Helixⁱ	100 – 104	Combined sources	5
Beta strandⁱ	106 – 108	Combined sources	3
Helixⁱ	112 – 131	Combined sources	20
Helixⁱ	141 – 143	Combined sources	3
Beta strandⁱ	144 – 146	Combined sources	3
Beta strandⁱ	152 – 154	Combined sources	3
Helixⁱ	163 – 168	Combined sources	6
Beta strandⁱ	171 – 173	Combined sources	3
Helixⁱ	190 – 192	Combined sources	3
Helixⁱ	195 – 197	Combined sources	3
Beta strandⁱ	201 – 203	Combined sources	3
Helixⁱ	207 – 223	Combined sources	17
Helixⁱ	228 – 230	Combined sources	3
Helixⁱ	234 – 242	Combined sources	9
Helixⁱ	249 – 251	Combined sources	3
Turnⁱ	252 – 255	Combined sources	4
Helixⁱ	258 – 267	Combined sources	10
Helixⁱ	272 – 274	Combined sources	3
Helixⁱ	278 – 292	Combined sources	15
Helixⁱ	294 – 296	Combined sources	3
Helixⁱ	297 – 309	Combined sources	13
Turnⁱ	310 – 312	Combined sources	3
Beta strandⁱ	533 – 542	Combined sources	10
Helixⁱ	575 – 577	Combined sources	3
Helixⁱ	584 – 593	Combined sources	10
Helixⁱ	599 – 604	Combined sources	6
Helixⁱ	609 – 618	Combined sources	10
Turnⁱ	619 – 622	Combined sources	4
Helixⁱ	624 – 643	Combined sources	20
Helixⁱ	646 – 655	Combined sources	10
Helixⁱ	659 – 668	Combined sources	10

Show more details

3D structure databases

SMRⁱ	Q13546
ModBaseⁱ	Search...
PDBe-KBⁱ	Search...

Family & Domainsⁱ

Domains and Repeats

Feature key	Position(s)	DescriptionActions	Graphical view	Length
Domainⁱ	17 – 289	Protein kinasePROSITE-ProRule annotationAdd BLAST		273
Domainⁱ	583 – 669	DeathPROSITE-ProRule annotationAdd BLAST		87

Region

Feature key	Position(s)	DescriptionActions	Graphical view	Length
Regionⁱ	290 – 582	Interaction with SQSTM11 PublicationAdd BLAST		293

Motif

Feature key	Position(s)	DescriptionActions	Graphical view	Length
Motifⁱ	531 – 547	RIP homotypic interaction motif (RHIM)1 PublicationAdd BLAST		17

Compositional bias

Feature key	Position(s)	DescriptionActions	Graphical view	Length
Compositional biasⁱ	411 – 414	Poly-Arg		4

Domainⁱ

The death domain mediates dimerization and activation of its kinase activity during necroptosis and apoptosis (PubMed:29440439). It engages other DD-containing proteins as well as a central (intermediate) region important for NF-kB activation and RHIM-dependent signaling (PubMed:10356400).2 Publications

Sequence similaritiesⁱ

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

Phylogenomic databases

eggNOGⁱ	KOG0192 Eukaryota COG0515 LUCA
Ensembl GeneTree More...GeneTreeⁱ	ENSGT00940000159347
HOGENOMⁱ	CLU_017229_0_0_1
InParanoidⁱ	Q13546
KEGG Orthology (KO) More...KOⁱ	K02861
OMAⁱ	NDFHIKI
Database of Orthologous Groups More...OrthoDBⁱ	346354at2759
PhylomeDBⁱ	Q13546
TreeFamⁱ	TF106506

Family and domain databases

Conserved Domains Database More...CDDⁱ	cd08777 Death_RIP1, 1 hit
InterProⁱ	View protein in InterPro IPR011029 DEATH-like_dom_sf IPR000488 Death_domain IPR011009 Kinase-like_dom_sf IPR000719 Prot_kinase_dom IPR025735 RHIM_dom IPR037934 RIP1_Death IPR001245 Ser-Thr/Tyr_kinase_cat_dom IPR008271 Ser/Thr_kinase_AS
Pfam protein domain database More...Pfamⁱ	View protein in Pfam PF00531 Death, 1 hit PF07714 Pkinase_Tyr, 1 hit PF12721 RHIM, 1 hit
PRINTSⁱ	PR00109 TYRKINASE
SMARTⁱ	View protein in SMART SM00005 DEATH, 1 hit SM00220 S_TKc, 1 hit
SUPFAMⁱ	SSF47986 SSF47986, 1 hit SSF56112 SSF56112, 1 hit
PROSITEⁱ	View protein in PROSITE PS50017 DEATH_DOMAIN, 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. Align Add to basket

Isoform 1 (identifier: Q13546-1) [UniParc]FASTA Add to basket

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

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        10         20         30         40         50
MQPDMSLNVI KMKSSDFLES AELDSGGFGK VSLCFHRTQG LMIMKTVYKG 
        60         70         80         90        100
PNCIEHNEAL LEEAKMMNRL RHSRVVKLLG VIIEEGKYSL VMEYMEKGNL 
       110        120        130        140        150
MHVLKAEMST PLSVKGRIIL EIIEGMCYLH GKGVIHKDLK PENILVDNDF 
       160        170        180        190        200
HIKIADLGLA SFKMWSKLNN EEHNELREVD GTAKKNGGTL YYMAPEHLND 
       210        220        230        240        250
VNAKPTEKSD VYSFAVVLWA IFANKEPYEN AICEQQLIMC IKSGNRPDVD 
       260        270        280        290        300
DITEYCPREI ISLMKLCWEA NPEARPTFPG IEEKFRPFYL SQLEESVEED 
       310        320        330        340        350
VKSLKKEYSN ENAVVKRMQS LQLDCVAVPS SRSNSATEQP GSLHSSQGLG 
       360        370        380        390        400
MGPVEESWFA PSLEHPQEEN EPSLQSKLQD EANYHLYGSR MDRQTKQQPR 
       410        420        430        440        450
QNVAYNREEE RRRRVSHDPF AQQRPYENFQ NTEGKGTAYS SAASHGNAVH 
       460        470        480        490        500
QPSGLTSQPQ VLYQNNGLYS SHGFGTRPLD PGTAGPRVWY RPIPSHMPSL 
       510        520        530        540        550
HNIPVPETNY LGNTPTMPFS SLPPTDESIK YTIYNSTGIQ IGAYNYMEIG 
       560        570        580        590        600
GTSSSLLDST NTNFKEEPAA KYQAIFDNTT SLTDKHLDPI RENLGKHWKN 
       610        620        630        640        650
CARKLGFTQS QIDEIDHDYE RDGLKEKVYQ MLQKWVMREG IKGATVGKLA 
       660        670 
QALHQCSRID LLSSLIYVSQ N

Length:671

Mass (Da):75,931

Last modified:February 1, 2005 - v3

Checksum:ⁱ976E2428D525A9B2

GO

Isoform 2 (identifier: Q13546-2) [UniParc]FASTA Add to basket

The sequence of this isoform differs from the canonical sequence as follows:
108-153: Missing.

« Hide

        10         20         30         40         50
MQPDMSLNVI KMKSSDFLES AELDSGGFGK VSLCFHRTQG LMIMKTVYKG 
        60         70         80         90        100
PNCIEHNEAL LEEAKMMNRL RHSRVVKLLG VIIEEGKYSL VMEYMEKGNL 
       110        120        130        140        150
MHVLKAEIAD LGLASFKMWS KLNNEEHNEL REVDGTAKKN GGTLYYMAPE 
       160        170        180        190        200
HLNDVNAKPT EKSDVYSFAV VLWAIFANKE PYENAICEQQ LIMCIKSGNR 
       210        220        230        240        250
PDVDDITEYC PREIISLMKL CWEANPEARP TFPGIEEKFR PFYLSQLEES 
       260        270        280        290        300
VEEDVKSLKK EYSNENAVVK RMQSLQLDCV AVPSSRSNSA TEQPGSLHSS 
       310        320        330        340        350
QGLGMGPVEE SWFAPSLEHP QEENEPSLQS KLQDEANYHL YGSRMDRQTK 
       360        370        380        390        400
QQPRQNVAYN REEERRRRVS HDPFAQQRPY ENFQNTEGKG TAYSSAASHG 
       410        420        430        440        450
NAVHQPSGLT SQPQVLYQNN GLYSSHGFGT RPLDPGTAGP RVWYRPIPSH 
       460        470        480        490        500
MPSLHNIPVP ETNYLGNTPT MPFSSLPPTD ESIKYTIYNS TGIQIGAYNY 
       510        520        530        540        550
MEIGGTSSSL LDSTNTNFKE EPAAKYQAIF DNTTSLTDKH LDPIRENLGK 
       560        570        580        590        600
HWKNCARKLG FTQSQIDEID HDYERDGLKE KVYQMLQKWV MREGIKGATV 
       610        620 
GKLAQALHQC SRIDLLSSLI YVSQN

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Length:625

Mass (Da):70,733

Checksum:ⁱ4D3780FB4A93FDB1

GO

Sequence cautionⁱ

The sequence BAG65471 differs from that shown. Reason: Erroneous initiation.Curated

Experimental Info

Feature key	Position(s)	DescriptionActions	Length
Sequence conflictⁱ	258	R → I in BAG36858 (PubMed:14702039).Curated	1
Sequence conflictⁱ	286	R → S in BAG36858 (PubMed:14702039).Curated	1
Sequence conflictⁱ	514	T → S in AAC50137 (PubMed:7538908).Curated	1

Natural variant

Feature key	Position(s)	DescriptionActions	Length
Natural variantⁱVAR_041039	64	A → V in a colorectal adenocarcinoma sample; somatic mutation. 1 PublicationCorresponds to variant dbSNP:rs774996232Ensembl.	1
Natural variantⁱVAR_041040	81	V → I in a colorectal adenocarcinoma sample; somatic mutation. 1 PublicationCorresponds to variant dbSNP:rs758268804Ensembl.	1
Natural variantⁱVAR_041041	220	A → V in a colorectal adenocarcinoma sample; somatic mutation. 1 PublicationCorresponds to variant dbSNP:rs759012409Ensembl.	1
Natural variantⁱVAR_021109	234	E → K1 PublicationCorresponds to variant dbSNP:rs17548383Ensembl.	1
Natural variantⁱVAR_083518	324	D → H Probable disease-associated variant found in patients with cleavage-resistant RIPK1-induced autoinflammatory syndrome; prevents cleavage by CASP8; increased kinase activity; increased inflammatory response. 2 Publications	1
Natural variantⁱVAR_083519	324	D → N Probable disease-associated variant found in patients with cleavage-resistant RIPK1-induced autoinflammatory syndrome; prevents cleavage by CASP8. 1 Publication	1
Natural variantⁱVAR_083520	324	D → Y Probable disease-associated variant found in patients with cleavage-resistant RIPK1-induced autoinflammatory syndrome; increased kinase activity; increased inflammatory response. 2 Publications	1
Natural variantⁱVAR_041042	404	A → S1 PublicationCorresponds to variant dbSNP:rs34872409Ensembl.	1
Natural variantⁱVAR_058285	438	A → V3 PublicationsCorresponds to variant dbSNP:rs3173519Ensembl.	1
Natural variantⁱVAR_041043	443	A → V1 PublicationCorresponds to variant dbSNP:rs35722193Ensembl.	1
Natural variantⁱVAR_041044	569	A → V1 PublicationCorresponds to variant dbSNP:rs55861377Ensembl.	1

Alternative sequence

Feature key	Position(s)	DescriptionActions	Graphical view	Length
Alternative sequenceⁱVSP_037690	108 – 153	Missing in isoform 2. 1 PublicationAdd BLAST		46

Sequence databases

Select the link destinations: EMBLⁱ GenBankⁱ DDBJⁱ Links Updated	U50062 mRNA Translation: AAC32232.1 AK314176 mRNA Translation: BAG36858.1 AK304701 mRNA Translation: BAG65471.1 Different initiation. AY682848 Genomic DNA Translation: AAT74626.1 AL031963 Genomic DNA No translation available. BC126254 mRNA Translation: AAI26255.1 BC126256 mRNA Translation: AAI26257.1 AB208926 mRNA Translation: BAD92163.1 U25994 mRNA Translation: AAC50137.1
The Consensus CDS (CCDS) project More...CCDSⁱ	CCDS4482.1 [Q13546-1]
PIRⁱ	T09479
NCBI Reference Sequences More...RefSeqⁱ	NP_003795.2, NM_003804.4 [Q13546-1] XP_005249514.2, XM_005249457.3

Genome annotation databases

Ensemblⁱ	ENST00000259808; ENSP00000259808; ENSG00000137275 [Q13546-1] ENST00000380409; ENSP00000369773; ENSG00000137275 [Q13546-1]
GeneIDⁱ	8737
KEGGⁱ	hsa:8737
UCSC genome browser More...UCSCⁱ	uc003mux.4 human [Q13546-1]

Keywords - Coding sequence diversityⁱ

Alternative splicing, Polymorphism

Similar proteinsⁱ

100% Identity
90% Identity
50% Identity

Protein	Similar proteins		Species	Score	Length	Source
Q13546	Receptor (TNFRSF)-interacting serine-threonine kinase 1, isoform CRA_a		HUMAN		671	UniRef100_Q13546
UPI0000579D75		HUMAN		508

Protein	Similar proteins		Species	Score	Length	Source
Q13546	Receptor (TNFRSF)-interacting serine-threonine kinase 1, isoform CRA_a		HUMAN		671	UniRef90_Q13546
Uncharacterized protein		PAPAN		776
Uncharacterized protein		RHIBE		672
Receptor interacting serine/threonine kinase 1		MACMU		671
Uncharacterized protein		RHIRO		671
+43

Protein	Similar proteins		Species	Score	Length	Source
Q13546	Receptor (TNFRSF)-interacting serine-threonine kinase 1, isoform CRA_a		HUMAN		671	UniRef50_Q13546
Uncharacterized protein		PAPAN		776
Uncharacterized protein		RHIBE		672
Receptor interacting serine/threonine kinase 1		MACFA		671
RIPK1 isoform 3		PONAB		671
+84

Cross-referencesⁱ

Web resourcesⁱ

SeattleSNPs

Sequence databases

Select the link destinations: EMBLⁱ GenBankⁱ DDBJⁱ Links Updated	U50062 mRNA Translation: AAC32232.1 AK314176 mRNA Translation: BAG36858.1 AK304701 mRNA Translation: BAG65471.1 Different initiation. AY682848 Genomic DNA Translation: AAT74626.1 AL031963 Genomic DNA No translation available. BC126254 mRNA Translation: AAI26255.1 BC126256 mRNA Translation: AAI26257.1 AB208926 mRNA Translation: BAD92163.1 U25994 mRNA Translation: AAC50137.1
CCDSⁱ	CCDS4482.1 [Q13546-1]
PIRⁱ	T09479
RefSeqⁱ	NP_003795.2, NM_003804.4 [Q13546-1] XP_005249514.2, XM_005249457.3

3D structure databases

Select the link destinations: Protein Data Bank Europe More...PDBeⁱ Protein Data Bank RCSB More...RCSB PDBⁱ Protein Data Bank Japan More...PDBjⁱ Links Updated	PDB entry	Method	Resolution (Å)	Chain	Positions	PDBsum
	4ITH	X-ray	2.25	A/B	1-294	[»]
	4ITI	X-ray	2.86	A/B	1-294	[»]
	4ITJ	X-ray	1.80	A/B	1-294	[»]
	4NEU	X-ray	2.57	A/B	1-324	[»]
	5HX6	X-ray	2.23	A/B	1-294	[»]
	5TX5	X-ray	2.56	A/B	1-294	[»]
	5V7Z	NMR	-	B/D/F/H	532-549	[»]
	6AC5	X-ray	1.45	A	561-671	[»]
	6C3E	X-ray	2.60	A/B	2-294	[»]
	6C4D	X-ray	2.52	A/B/C/D	2-294	[»]
	6HHO	X-ray	3.49	A/B	1-294	[»]
	6NW2	X-ray	2.00	A/B	1-294	[»]
	6NYH	X-ray	2.10	A/B	1-294	[»]
	6OCQ	X-ray	2.79	A/B	1-294	[»]
	6R5F	X-ray	3.25	A/B/C/D	1-294	[»]
	6RLN	X-ray	2.87	A/B	1-294	[»]
SMRⁱ	Q13546
ModBaseⁱ	Search...
PDBe-KBⁱ	Search...

Protein-protein interaction databases

BioGRIDⁱ	114274, 101 interactors
ComplexPortalⁱ	CPX-1907 Ripoptosome
CORUMⁱ	Q13546
DIPⁱ	DIP-433N
IntActⁱ	Q13546, 75 interactors
MINTⁱ	Q13546
STRINGⁱ	9606.ENSP00000259808

Chemistry databases

BindingDBⁱ	Q13546
ChEMBLⁱ	CHEMBL5464
DrugBankⁱ	DB12010 Fostamatinib
DrugCentralⁱ	Q13546
GuidetoPHARMACOLOGYⁱ	2189

PTM databases

iPTMnetⁱ	Q13546
MetOSiteⁱ	Q13546
PhosphoSitePlusⁱ	Q13546

Polymorphism and mutation databases

BioMutaⁱ	RIPK1
DMDMⁱ	60393639

Proteomic databases

CPTACⁱ	CPTAC-1053 CPTAC-900 CPTAC-901 CPTAC-902
EPDⁱ	Q13546
jPOSTⁱ	Q13546
MassIVEⁱ	Q13546
MaxQBⁱ	Q13546
PaxDbⁱ	Q13546
PeptideAtlasⁱ	Q13546
PRIDEⁱ	Q13546
ProteomicsDBⁱ	59527 [Q13546-1] 59528 [Q13546-2]

Protocols and materials databases

Antibodypediaⁱ	4145 595 antibodies
The DNASU plasmid repository More...DNASUⁱ	8737

Genome annotation databases

Ensemblⁱ	ENST00000259808; ENSP00000259808; ENSG00000137275 [Q13546-1] ENST00000380409; ENSP00000369773; ENSG00000137275 [Q13546-1]
GeneIDⁱ	8737
KEGGⁱ	hsa:8737
UCSCⁱ	uc003mux.4 human [Q13546-1]

Organism-specific databases

CTDⁱ	8737
DisGeNETⁱ	8737
EuPathDBⁱ	HostDB:ENSG00000137275.13
GeneCardsⁱ	RIPK1
HGNCⁱ	HGNC:10019 RIPK1
HPAⁱ	ENSG00000137275 Low tissue specificity
MalaCardsⁱ	RIPK1
MIMⁱ	603453 gene 618108 phenotype
neXtProtⁱ	NX_Q13546
OpenTargetsⁱ	ENSG00000137275
PharmGKBⁱ	PA34394
GenAtlas: human gene database More...GenAtlasⁱ	Search...

Phylogenomic databases

eggNOGⁱ	KOG0192 Eukaryota COG0515 LUCA
GeneTreeⁱ	ENSGT00940000159347
HOGENOMⁱ	CLU_017229_0_0_1
InParanoidⁱ	Q13546
KOⁱ	K02861
OMAⁱ	NDFHIKI
OrthoDBⁱ	346354at2759
PhylomeDBⁱ	Q13546
TreeFamⁱ	TF106506

Enzyme and pathway databases

BRENDAⁱ	2.7.10.2 2681
Reactomeⁱ	R-HSA-140534 Caspase activation via Death Receptors in the presence of ligand R-HSA-168927 TICAM1, RIP1-mediated IKK complex recruitment R-HSA-1810476 RIP-mediated NFkB activation via ZBP1 R-HSA-2562578 TRIF-mediated programmed cell death R-HSA-3295583 TRP channels R-HSA-3371378 Regulation by c-FLIP R-HSA-5213460 RIPK1-mediated regulated necrosis R-HSA-5218900 CASP8 activity is inhibited R-HSA-5357786 TNFR1-induced proapoptotic signaling R-HSA-5357905 Regulation of TNFR1 signaling R-HSA-5357956 TNFR1-induced NFkappaB signaling pathway R-HSA-5675482 Regulation of necroptotic cell death R-HSA-5689880 Ub-specific processing proteases R-HSA-5689896 Ovarian tumor domain proteases R-HSA-69416 Dimerization of procaspase-8 R-HSA-75893 TNF signaling R-HSA-9013957 TLR3-mediated TICAM1-dependent programmed cell death R-HSA-933543 NF-kB activation through FADD/RIP-1 pathway mediated by caspase-8 and -10 R-HSA-937041 IKK complex recruitment mediated by RIP1
SignaLinkⁱ	Q13546
SIGNORⁱ	Q13546

Miscellaneous databases

BioGRID-ORCSⁱ	8737 16 hits in 818 CRISPR screens
ChiTaRSⁱ	RIPK1 human
GeneWikiⁱ	RIPK1
GenomeRNAiⁱ	8737
Pharosⁱ	Q13546 Tchem
Protein Ontology More...PROⁱ	PR:Q13546
RNActⁱ	Q13546 protein
SOURCEⁱ	Search...

Gene expression databases

Bgeeⁱ	ENSG00000137275 Expressed in right lobe of liver and 183 other tissues
ExpressionAtlasⁱ	Q13546 baseline and differential
Genevisibleⁱ	Q13546 HS

Family and domain databases

CDDⁱ	cd08777 Death_RIP1, 1 hit
InterProⁱ	View protein in InterPro IPR011029 DEATH-like_dom_sf IPR000488 Death_domain IPR011009 Kinase-like_dom_sf IPR000719 Prot_kinase_dom IPR025735 RHIM_dom IPR037934 RIP1_Death IPR001245 Ser-Thr/Tyr_kinase_cat_dom IPR008271 Ser/Thr_kinase_AS
Pfamⁱ	View protein in Pfam PF00531 Death, 1 hit PF07714 Pkinase_Tyr, 1 hit PF12721 RHIM, 1 hit
PRINTSⁱ	PR00109 TYRKINASE
SMARTⁱ	View protein in SMART SM00005 DEATH, 1 hit SM00220 S_TKc, 1 hit
SUPFAMⁱ	SSF47986 SSF47986, 1 hit SSF56112 SSF56112, 1 hit
PROSITEⁱ	View protein in PROSITE PS50017 DEATH_DOMAIN, 1 hit PS50011 PROTEIN_KINASE_DOM, 1 hit PS00108 PROTEIN_KINASE_ST, 1 hit
ProtoNetⁱ	Search...
MobiDBⁱ	Search...

Entry informationⁱ

Entry nameⁱ	RIPK1_HUMAN
Accessionⁱ	Q13546Primary (citable) accession number: Q13546 Secondary accession number(s): A0AV89 , B2RAG1, B4E3F9, Q13180, Q59H33
Entry historyⁱ	Integrated into UniProtKB/Swiss-Prot:	November 1, 1997
	Last sequence update:	February 1, 2005
	Last modified:	June 17, 2020
	This is version 216 of the entry and version 3 of the sequence. See complete history.
Entry statusⁱ	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.

Miscellaneousⁱ

Keywords - Technical termⁱ

3D-structure, Reference proteome

Documents

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

UniProtKB

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UniProtKB - Q13546 (RIPK1_HUMAN)

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Receptor-interacting serine/threonine-protein kinase 1

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<p>This section provides any useful information about the protein, mostly biological knowledge.<p><a href='/help/function_section' target='_top'>More...</a></p>Functioni

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GO - Biological processi

Enzyme and pathway databases

<p>This section provides information about the protein and gene name(s) and synonym(s) and about the organism that is the source of the protein sequence.<p><a href='/help/names_and_taxonomy_section' target='_top'>More...</a></p>Names & Taxonomyi

Organism-specific databases

<p>This section provides information on the location and the topology of the mature protein in the cell.<p><a href='/help/subcellular_location_section' target='_top'>More...</a></p>Subcellular locationi

Plasma membrane

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Endosome

Mitochondrion

Plasma Membrane

Other locations

Keywords - Cellular componenti

<p>This section provides information on the disease(s) and phenotype(s) associated with a protein.<p><a href='/help/pathology_and_biotech_section' target='_top'>More...</a></p>Pathology & Biotechi

Mutagenesis

Organism-specific databases

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Chemistry databases

Polymorphism and mutation databases

<p>This section describes post-translational modifications (PTMs) and/or processing events.<p><a href='/help/ptm_processing_section' target='_top'>More...</a></p>PTM / Processingi

Molecule processing

Amino acid modifications

Sites

Keywords - PTMi

Proteomic databases

PTM databases

<p>This section provides information on the expression of a gene at the mRNA or protein level in cells or in tissues of multicellular organisms.<p><a href='/help/expression_section' target='_top'>More...</a></p>Expressioni

Gene expression databases

Organism-specific databases

<p>This section provides information on the quaternary structure of a protein and on interaction(s) with other proteins or protein complexes.<p><a href='/help/interaction_section' target='_top'>More...</a></p>Interactioni

Q13546

GO - Molecular functioni

Protein-protein interaction databases

Chemistry databases

Miscellaneous databases

<p>This section provides information on the tertiary and secondary structure of a protein.<p><a href='/help/structure_section' target='_top'>More...</a></p>Structurei

Secondary structure

3D structure databases

<p>This section provides information on sequence similarities with other proteins and the domain(s) present in a protein.<p><a href='/help/family_and_domains_section' target='_top'>More...</a></p>Family & Domainsi

Domains and Repeats

Region

Motif

Compositional bias

<p>This subsection of the 'Family and domains' section provides information about the sequence similarity with other proteins.<p><a href='/help/sequence_similarities' target='_top'>More...</a></p>Sequence similaritiesi

Phylogenomic databases

Family and domain databases

<p>This subsection of the 'Sequence' section reports difference(s) between the protein sequence shown in the UniProtKB entry and other available protein sequences derived from the same gene.<p><a href='/help/sequence_caution' target='_top'>More...</a></p>Sequence cautioni

Experimental Info

Natural variant

Alternative sequence

Sequence databases

Genome annotation databases

Keywords - Coding sequence diversityi

<p>This section is used to point to information related to entries and found in data collections other than UniProtKB.<p><a href='/help/cross_references_section' target='_top'>More...</a></p>Cross-referencesi

<p>This subsection of the <a href="http://www.uniprot.org/manual/cross%5Freferences%5Fsection">Cross-references</a> section provides links to various web resources that are relevant for a specific protein.<p><a href='/help/web_resource' target='_top'>More...</a></p>Web resourcesi

Sequence databases

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Proteomic databases

Protocols and materials databases

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Functionⁱ

Catalytic activityⁱ

GO - Molecular functionⁱ

GO - Biological processⁱ

Names & Taxonomyⁱ

Subcellular locationⁱ

Keywords - Cellular componentⁱ

Pathology & Biotechⁱ

PTM / Processingⁱ

Keywords - PTMⁱ

Expressionⁱ

Interactionⁱ

GO - Molecular functionⁱ

Structureⁱ

Family & Domainsⁱ

Sequence similaritiesⁱ

Sequence cautionⁱ

Keywords - Coding sequence diversityⁱ

Cross-referencesⁱ

Web resourcesⁱ

Entry informationⁱ

Miscellaneousⁱ

Keywords - Technical termⁱ