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Protein

Tumor necrosis factor receptor superfamily member 1A

Gene

TNFRSF1A

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

Functioni

Receptor for TNFSF2/TNF-alpha and homotrimeric TNFSF1/lymphotoxin-alpha. The adapter molecule FADD recruits caspase-8 to the activated receptor. The resulting death-inducing signaling complex (DISC) performs caspase-8 proteolytic activation which initiates the subsequent cascade of caspases (aspartate-specific cysteine proteases) mediating apoptosis. Contributes to the induction of non-cytocidal TNF effects including anti-viral state and activation of the acid sphingomyelinase.

GO - Molecular functioni

  • identical protein binding Source: IntAct
  • tumor necrosis factor-activated receptor activity Source: UniProtKB
  • tumor necrosis factor binding Source: GO_Central

GO - Biological processi

Keywordsi

Molecular functionReceptor
Biological processApoptosis, Host-virus interaction

Enzyme and pathway databases

ReactomeiR-HSA-5357786 TNFR1-induced proapoptotic signaling
R-HSA-5357905 Regulation of TNFR1 signaling
R-HSA-5357956 TNFR1-induced NFkappaB signaling pathway
R-HSA-5626978 TNFR1-mediated ceramide production
R-HSA-5669034 TNFs bind their physiological receptors
R-HSA-6783783 Interleukin-10 signaling
R-HSA-75893 TNF signaling
SIGNORiP19438

Names & Taxonomyi

Protein namesi
Recommended name:
Tumor necrosis factor receptor superfamily member 1A
Alternative name(s):
Tumor necrosis factor receptor 1
Short name:
TNF-R1
Tumor necrosis factor receptor type I
Short name:
TNF-RI
Short name:
TNFR-I
p55
p60
CD_antigen: CD120a
Cleaved into the following 2 chains:
Gene namesi
Name:TNFRSF1A
Synonyms:TNFAR, TNFR1
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 12

Organism-specific databases

EuPathDBiHostDB:ENSG00000067182.7
HGNCiHGNC:11916 TNFRSF1A
MIMi191190 gene
neXtProtiNX_P19438

Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

Topology

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Topological domaini30 – 211ExtracellularSequence analysisAdd BLAST182
Transmembranei212 – 232HelicalSequence analysisAdd BLAST21
Topological domaini233 – 455CytoplasmicSequence analysisAdd BLAST223

Keywords - Cellular componenti

Cell membrane, Golgi apparatus, Membrane, Secreted

Pathology & Biotechi

Involvement in diseasei

Familial hibernian fever (FHF)5 Publications
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionA hereditary periodic fever syndrome characterized by recurrent fever, abdominal pain, localized tender skin lesions and myalgia. Reactive amyloidosis is the main complication and occurs in 25% of cases.
See also OMIM:142680
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_01932951H → Q in FHF. 1 PublicationCorresponds to variant dbSNP:rs104895254EnsemblClinVar.1
Natural variantiVAR_01341059C → R in FHF. 1 PublicationCorresponds to variant dbSNP:rs104895217EnsemblClinVar.1
Natural variantiVAR_01930259C → S in FHF. 2 PublicationsCorresponds to variant dbSNP:rs104895223EnsemblClinVar.1
Natural variantiVAR_01930362C → G in FHF. 1 PublicationCorresponds to variant dbSNP:rs104895225EnsemblClinVar.1
Natural variantiVAR_01341162C → Y in FHF. 1 PublicationCorresponds to variant dbSNP:rs104895218EnsemblClinVar.1
Natural variantiVAR_01933075P → L in FHF; may be a polymorphism. 2 PublicationsCorresponds to variant dbSNP:rs4149637EnsemblClinVar.1
Natural variantiVAR_01341279T → M in FHF. 1 PublicationCorresponds to variant dbSNP:rs104895219EnsemblClinVar.1
Natural variantiVAR_01341381C → F in FHF. 1 PublicationCorresponds to variant dbSNP:rs104895220EnsemblClinVar.1
Natural variantiVAR_01930499C → S in FHF. 2 PublicationsCorresponds to variant dbSNP:rs104895228EnsemblClinVar.1
Natural variantiVAR_019331115S → G in FHF. 1 Publication1
Natural variantiVAR_013414117C → R in FHF. 1 PublicationCorresponds to variant dbSNP:rs104895221EnsemblClinVar.1
Natural variantiVAR_013415117C → Y in FHF. 1 PublicationCorresponds to variant dbSNP:rs104895222EnsemblClinVar.1
Natural variantiVAR_019305121R → P in FHF. 1 PublicationCorresponds to variant dbSNP:rs4149584EnsemblClinVar.1
Natural variantiVAR_019332121R → Q in FHF; unknown pathological significance. 2 PublicationsCorresponds to variant dbSNP:rs4149584EnsemblClinVar.1
Multiple sclerosis 5 (MS5)1 Publication
Disease susceptibility is associated with variations affecting the gene represented in this entry. An intronic mutation affecting alternative splicing and skipping of exon 6 directs increased expression of isoform 4 a transcript encoding a C-terminally truncated protein which is secreted and may function as a TNF antagonist.
Disease descriptionA multifactorial, inflammatory, demyelinating disease of the central nervous system. Sclerotic lesions are characterized by perivascular infiltration of monocytes and lymphocytes and appear as indurated areas in pathologic specimens (sclerosis in plaques). The pathological mechanism is regarded as an autoimmune attack of the myelin sheath, mediated by both cellular and humoral immunity. Clinical manifestations include visual loss, extra-ocular movement disorders, paresthesias, loss of sensation, weakness, dysarthria, spasticity, ataxia and bladder dysfunction. Genetic and environmental factors influence susceptibility to the disease.
See also OMIM:614810

Keywords - Diseasei

Amyloidosis, Disease mutation

Organism-specific databases

DisGeNETi7132
MalaCardsiTNFRSF1A
MIMi142680 phenotype
614810 phenotype
OpenTargetsiENSG00000067182
Orphaneti329967 Intermittent hydrarthrosis
802 Multiple sclerosis
32960 Tumor necrosis factor receptor 1 associated periodic syndrome
PharmGKBiPA36609

Chemistry databases

ChEMBLiCHEMBL3378

Polymorphism and mutation databases

BioMutaiTNFRSF1A
DMDMi135959

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Signal peptidei1 – 291 PublicationAdd BLAST29
ChainiPRO_000003454330 – 455Tumor necrosis factor receptor superfamily member 1A, membrane formAdd BLAST426
ChainiPRO_000003454441 – 201Tumor necrosis factor-binding protein 1Add BLAST161

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Disulfide bondi44 ↔ 58
Glycosylationi54N-linked (GlcNAc...) asparagineSequence analysis1
Disulfide bondi59 ↔ 72
Disulfide bondi62 ↔ 81
Disulfide bondi84 ↔ 99
Disulfide bondi102 ↔ 117
Disulfide bondi105 ↔ 125
Disulfide bondi127 ↔ 143
Glycosylationi145N-linked (GlcNAc...) asparagineSequence analysis1
Disulfide bondi146 ↔ 158
Disulfide bondi149 ↔ 166
Glycosylationi151N-linked (GlcNAc...) asparagineSequence analysis1
Disulfide bondi168 ↔ 179
Disulfide bondi182 ↔ 195
Disulfide bondi185 ↔ 191

Post-translational modificationi

The soluble form is produced from the membrane form by proteolytic processing.

Keywords - PTMi

Cleavage on pair of basic residues, Disulfide bond, Glycoprotein

Proteomic databases

MaxQBiP19438
PaxDbiP19438
PeptideAtlasiP19438
PRIDEiP19438

PTM databases

iPTMnetiP19438
PhosphoSitePlusiP19438

Miscellaneous databases

PMAP-CutDBP19438

Expressioni

Gene expression databases

BgeeiENSG00000067182
CleanExiHS_TNFRSF1A
ExpressionAtlasiP19438 baseline and differential
GenevisibleiP19438 HS

Organism-specific databases

HPAiCAB010309
HPA004102

Interactioni

Subunit structurei

Binding of TNF to the extracellular domain leads to homotrimerization. The aggregated death domains provide a novel molecular interface that interacts specifically with the death domain of TRADD. Various TRADD-interacting proteins such as TRAFS, RIPK1 and possibly FADD, are recruited to the complex by their association with TRADD. This complex activates at least two distinct signaling cascades, apoptosis and NF-kappa-B signaling. Interacts with BAG4, BABAM2, FEM1B, GRB2, SQSTM1 and TRPC4AP. Interacts directly with NOL3 (via CARD domain); inhibits TNF-signaling pathway (By similarity).By similarity6 Publications
(Microbial infection) Interacts with mumps virus protein SH; this interaction inhibits downstream NF-kappa-B pathway activation (PubMed:28659487). Interacts with HCV core protein. Interacts with human cytomegalovirus/HHV-5 protein UL138 (PubMed:21976655).3 Publications

Binary interactionsi

Show more details

GO - Molecular functioni

  • identical protein binding Source: IntAct
  • tumor necrosis factor binding Source: GO_Central

Protein-protein interaction databases

BioGridi112986, 161 interactors
CORUMiP19438
DIPiDIP-407N
IntActiP19438, 36 interactors
MINTiP19438
STRINGi9606.ENSP00000162749

Chemistry databases

BindingDBiP19438

Structurei

Secondary structure

1455
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Beta strandi48 – 50Combined sources3
Beta strandi52 – 54Combined sources3
Beta strandi58 – 60Combined sources3
Beta strandi66 – 70Combined sources5
Beta strandi80 – 83Combined sources4
Beta strandi92 – 94Combined sources3
Helixi107 – 109Combined sources3
Beta strandi112 – 115Combined sources4
Beta strandi124 – 126Combined sources3
Beta strandi131 – 137Combined sources7
Beta strandi140 – 145Combined sources6
Beta strandi152 – 156Combined sources5
Beta strandi160 – 162Combined sources3
Beta strandi165 – 168Combined sources4
Beta strandi172 – 175Combined sources4
Beta strandi178 – 181Combined sources4
Helixi182 – 184Combined sources3
Helixi192 – 195Combined sources4
Helixi357 – 365Combined sources9
Helixi371 – 378Combined sources8
Helixi382 – 391Combined sources10
Helixi396 – 410Combined sources15
Helixi417 – 427Combined sources11
Helixi431 – 441Combined sources11

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
1EXTX-ray1.85A/B41-201[»]
1FT4X-ray2.90A/B41-201[»]
1ICHNMR-A345-455[»]
1NCFX-ray2.25A/B41-201[»]
1TNRX-ray2.85R44-182[»]
ProteinModelPortaliP19438
SMRiP19438
ModBaseiSearch...
MobiDBiSearch...

Miscellaneous databases

EvolutionaryTraceiP19438

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Repeati43 – 82TNFR-Cys 1Add BLAST40
Repeati83 – 125TNFR-Cys 2Add BLAST43
Repeati126 – 166TNFR-Cys 3Add BLAST41
Repeati167 – 196TNFR-Cys 4Add BLAST30
Domaini356 – 441DeathPROSITE-ProRule annotationAdd BLAST86

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni338 – 348N-SMase activation domain (NSD)Add BLAST11

Domaini

The domain that induces A-SMASE is probably identical to the death domain. The N-SMASE activation domain (NSD) is both necessary and sufficient for activation of N-SMASE.
Both the cytoplasmic membrane-proximal region and the C-terminal region containing the death domain are involved in the interaction with TRPC4AP.By similarity

Keywords - Domaini

Repeat, Signal, Transmembrane, Transmembrane helix

Phylogenomic databases

eggNOGiENOG410IXBX Eukaryota
ENOG4111YG2 LUCA
GeneTreeiENSGT00530000064001
HOGENOMiHOG000202854
HOVERGENiHBG058842
InParanoidiP19438
KOiK03158
OMAiGCLEDIE
OrthoDBiEOG091G07LE
PhylomeDBiP19438
TreeFamiTF333916

Family and domain databases

CDDicd08313 Death_TNFR1, 1 hit
cd10576 TNFRSF1A, 1 hit
InterProiView protein in InterPro
IPR011029 DEATH-like_dom_sf
IPR000488 Death_domain
IPR001368 TNFR/NGFR_Cys_rich_reg
IPR020419 TNFR_1A
IPR033994 TNFRSF1A_death
IPR033993 TNFRSF1A_N
PfamiView protein in Pfam
PF00531 Death, 1 hit
PF00020 TNFR_c6, 3 hits
PRINTSiPR01918 TNFACTORR1A
SMARTiView protein in SMART
SM00005 DEATH, 1 hit
SM00208 TNFR, 4 hits
SUPFAMiSSF47986 SSF47986, 1 hit
PROSITEiView protein in PROSITE
PS50017 DEATH_DOMAIN, 1 hit
PS00652 TNFR_NGFR_1, 3 hits
PS50050 TNFR_NGFR_2, 3 hits

Sequences (5)i

Sequence statusi: Complete.

Sequence processingi: The displayed sequence is further processed into a mature form.

This entry describes 5 isoformsi produced by alternative splicing. AlignAdd to basket

Isoform 1 (identifier: P19438-1) [UniParc]FASTAAdd to basket
Also known as: FL-TNFR1

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
MGLSTVPDLL LPLVLLELLV GIYPSGVIGL VPHLGDREKR DSVCPQGKYI
60 70 80 90 100
HPQNNSICCT KCHKGTYLYN DCPGPGQDTD CRECESGSFT ASENHLRHCL
110 120 130 140 150
SCSKCRKEMG QVEISSCTVD RDTVCGCRKN QYRHYWSENL FQCFNCSLCL
160 170 180 190 200
NGTVHLSCQE KQNTVCTCHA GFFLRENECV SCSNCKKSLE CTKLCLPQIE
210 220 230 240 250
NVKGTEDSGT TVLLPLVIFF GLCLLSLLFI GLMYRYQRWK SKLYSIVCGK
260 270 280 290 300
STPEKEGELE GTTTKPLAPN PSFSPTPGFT PTLGFSPVPS STFTSSSTYT
310 320 330 340 350
PGDCPNFAAP RREVAPPYQG ADPILATALA SDPIPNPLQK WEDSAHKPQS
360 370 380 390 400
LDTDDPATLY AVVENVPPLR WKEFVRRLGL SDHEIDRLEL QNGRCLREAQ
410 420 430 440 450
YSMLATWRRR TPRREATLEL LGRVLRDMDL LGCLEDIEEA LCGPAALPPA

PSLLR
Length:455
Mass (Da):50,495
Last modified:February 1, 1991 - v1
Checksum:i4CEFBA96D03B8225
GO
Isoform 2 (identifier: P19438-2) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     1-108: Missing.

Note: No experimental confirmation available.
Show »
Length:347
Mass (Da):38,651
Checksum:i8C629DAF8D7BA515
GO
Isoform 4 (identifier: P19438-4) [UniParc]FASTAAdd to basket
Also known as: Delta6-TNFR1

The sequence of this isoform differs from the canonical sequence as follows:
     184-455: NCKKSLECTK...ALPPAPSLLR → KHHSAVAPGH...LLHCLWEIDT

Note: Disease-associated isoform. Isoform 4 splicing pattern is driven by a variation in the exon 6/intron 6 boundary region that alters exon 6 splicing. Exon 6 skipping introduces a frameshift and the translation of a protein lacking the intracellular, the transmembrane and part of the extracellular domain.
Show »
Length:228
Mass (Da):25,577
Checksum:iA67C489AF6DDBFEC
GO
Isoform 3 (identifier: P19438-3) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     1-232: Missing.

Note: No experimental confirmation available.
Show »
Length:223
Mass (Da):24,794
Checksum:i31BDA9ACAEF12FC3
GO
Isoform 5 (identifier: P19438-5) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     184-218: NCKKSLECTKLCLPQIENVKGTEDSGTTVLLPLVI → KVLLCRPGWNAVARSRLTATSASQIQAILLLQPPK
     219-455: Missing.

Note: No experimental confirmation available.
Show »
Length:218
Mass (Da):24,194
Checksum:iFBDD906CEF26F405
GO

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti13L → LILPQ in BAG51763 (PubMed:14702039).Curated1
Sequence conflicti255K → E in BAG37891 (PubMed:14702039).Curated1
Sequence conflicti286S → G in BAG51763 (PubMed:14702039).Curated1
Sequence conflicti394R → L in BAF83777 (PubMed:14702039).Curated1
Sequence conflicti412Missing in AAA36756 (PubMed:2170974).Curated1
Sequence conflicti443 – 446GPAA → APP in AAA36756 (PubMed:2170974).Curated4

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_01932951H → Q in FHF. 1 PublicationCorresponds to variant dbSNP:rs104895254EnsemblClinVar.1
Natural variantiVAR_01341059C → R in FHF. 1 PublicationCorresponds to variant dbSNP:rs104895217EnsemblClinVar.1
Natural variantiVAR_01930259C → S in FHF. 2 PublicationsCorresponds to variant dbSNP:rs104895223EnsemblClinVar.1
Natural variantiVAR_01930362C → G in FHF. 1 PublicationCorresponds to variant dbSNP:rs104895225EnsemblClinVar.1
Natural variantiVAR_01341162C → Y in FHF. 1 PublicationCorresponds to variant dbSNP:rs104895218EnsemblClinVar.1
Natural variantiVAR_01933075P → L in FHF; may be a polymorphism. 2 PublicationsCorresponds to variant dbSNP:rs4149637EnsemblClinVar.1
Natural variantiVAR_01341279T → M in FHF. 1 PublicationCorresponds to variant dbSNP:rs104895219EnsemblClinVar.1
Natural variantiVAR_01341381C → F in FHF. 1 PublicationCorresponds to variant dbSNP:rs104895220EnsemblClinVar.1
Natural variantiVAR_01930499C → S in FHF. 2 PublicationsCorresponds to variant dbSNP:rs104895228EnsemblClinVar.1
Natural variantiVAR_019331115S → G in FHF. 1 Publication1
Natural variantiVAR_013414117C → R in FHF. 1 PublicationCorresponds to variant dbSNP:rs104895221EnsemblClinVar.1
Natural variantiVAR_013415117C → Y in FHF. 1 PublicationCorresponds to variant dbSNP:rs104895222EnsemblClinVar.1
Natural variantiVAR_019305121R → P in FHF. 1 PublicationCorresponds to variant dbSNP:rs4149584EnsemblClinVar.1
Natural variantiVAR_019332121R → Q in FHF; unknown pathological significance. 2 PublicationsCorresponds to variant dbSNP:rs4149584EnsemblClinVar.1
Natural variantiVAR_011813305P → T. Corresponds to variant dbSNP:rs1804532Ensembl.1

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_0371541 – 232Missing in isoform 3. 1 PublicationAdd BLAST232
Alternative sequenceiVSP_0371531 – 108Missing in isoform 2. 1 PublicationAdd BLAST108
Alternative sequenceiVSP_044949184 – 455NCKKS…PSLLR → KHHSAVAPGHFLWSLPFIPP LHWFNVSLPTVEVQALLHCL WEIDT in isoform 4. CuratedAdd BLAST272
Alternative sequenceiVSP_047613184 – 218NCKKS…LPLVI → KVLLCRPGWNAVARSRLTAT SASQIQAILLLQPPK in isoform 5. 1 PublicationAdd BLAST35
Alternative sequenceiVSP_047614219 – 455Missing in isoform 5. 1 PublicationAdd BLAST237

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
M58286 mRNA Translation: AAA36753.1
M33294 mRNA Translation: AAA03210.1
M63121 mRNA Translation: AAA36754.1
X55313 mRNA Translation: CAA39021.1
M60275 mRNA Translation: AAA36756.1
M75866, M75864, M75865 Genomic DNA Translation: AAA61201.1
AY131997 Genomic DNA Translation: AAM77802.1
AK056611 mRNA Translation: BAG51763.1
AK291088 mRNA Translation: BAF83777.1
AK298729 mRNA Translation: BAG60879.1
AK304517 mRNA Translation: BAG65321.1
AK315509 mRNA Translation: BAG37891.1
EU927389 mRNA Translation: ACH57451.1
AC006057 Genomic DNA No translation available.
CH471116 Genomic DNA Translation: EAW88805.1
CH471116 Genomic DNA Translation: EAW88806.1
BC010140 mRNA Translation: AAH10140.1
CCDSiCCDS8542.1 [P19438-1]
PIRiA38208 GQHUT1
RefSeqiNP_001056.1, NM_001065.3 [P19438-1]
NP_001333020.1, NM_001346091.1 [P19438-2]
NP_001333021.1, NM_001346092.1
UniGeneiHs.279594
Hs.713833

Genome annotation databases

EnsembliENST00000162749; ENSP00000162749; ENSG00000067182 [P19438-1]
ENST00000366159; ENSP00000380389; ENSG00000067182 [P19438-5]
GeneIDi7132
KEGGihsa:7132
UCSCiuc001qnu.4 human [P19438-1]

Keywords - Coding sequence diversityi

Alternative splicing, Polymorphism

Similar proteinsi

Entry informationi

Entry nameiTNR1A_HUMAN
AccessioniPrimary (citable) accession number: P19438
Secondary accession number(s): A8K4X3
, B2RDE4, B3KPQ1, B4DQB7, B4E309, B5M0B5, D3DUR1, Q9UCA4
Entry historyiIntegrated into UniProtKB/Swiss-Prot: February 1, 1991
Last sequence update: February 1, 1991
Last modified: May 23, 2018
This is version 226 of the entry and version 1 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, Direct protein sequencing, Reference proteome

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