Reviewed, UniProtKB/Swiss-Prot P20333 (TNR1B_HUMAN)

Names and origin

Protein names

Recommended name:
    Tumor necrosis factor receptor superfamily member 1B
Alternative name(s):
    Tumor necrosis factor receptor 2
      Short name=TNF-R2
    Tumor necrosis factor receptor type II
    p75
    p80 TNF-alpha receptor
    CD_antigen=CD120b
    INN=Etanercept
Cleaved into the following 2 chains:
    1- Recommended name:
            Tumor necrosis factor receptor superfamily member 1b, membrane form
    2- Recommended name:
            Tumor necrosis factor-binding protein 2
        Alternative name(s):
            TBPII
            TBP-2

Gene names

Name:	TNFRSF1B
Synonyms:	TNFBR, TNFR2

Organism

Homo sapiens (Human)

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

Protein attributes

Sequence length	461 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is further processed into a mature form.
Protein existence	Evidence at protein level.

General annotation (Comments)

Function	Receptor with high affinity for TNFSF2/TNF-alpha and approximately 5-fold lower affinity for homotrimeric TNFSF1/lymphotoxin-alpha. The TRAF1/TRAF2 complex recruits the apoptotic suppressors BIRC2 and BIRC3 to TNFRSF1B/TNFR2. This receptor mediates most of the metabolic effects of TNF-alpha. Isoform 2 blocks TNF-alpha-induced apoptosis, which suggests that it regulates TNF-alpha function by antagonizing its biological activity.
Subunit structure	Binds to TRAF2.
Subcellular location	Isoform 1: Cell membrane; Single-pass type I membrane protein. Isoform 2: Secreted. Tumor necrosis factor-binding protein 2: Secreted.
Post-translational modification	Phosphorylated; mainly on serine residues and with a very low level on threonine residues. A soluble form (tumor necrosis factor binding protein 2) is produced from the membrane form by proteolytic processing.
Pharmaceutical use	Available under the name Enbrel (Immunex and Wyeth-Ayerst). Used to treat moderate to severe rheumatoid arthritis (RA). Enbrel consist of the extracellular ligand-binding portion of TNFRSF1B linked to an immunoglobulin Fc chain. It binds to TNF-alpha and blocks its interactions with receptors.
Sequence similarities	Contains 4 TNFR-Cys repeats.

Ontologies

Keywords
Biological process	Apoptosis
Cellular component	Cell membrane Membrane Secreted
Coding sequence diversity	Alternative splicing Polymorphism
Domain	Repeat Signal Transmembrane
Molecular function	Receptor
PTM	Glycoprotein Phosphoprotein
Technical term	3D-structure Direct protein sequencing Pharmaceutical
Gene Ontology (GO)
Molecular function	tumor necrosis factor receptor activity Traceable author statement. Source: ProtInc
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
Traf1	P39428	1	EBI-358983,EBI-520123	From a different organism.
TRAF2	Q12933	2	EBI-358983,EBI-355744

Alternative products

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

Isoform 1 (identifier: P20333-1)

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: P20333-2)

Also known as: DS-TNFR2(Delta7,8); sTNFR2;

The sequence of this isoform differs from the canonical sequence as follows:
     263-268: GLIVGV → ASLACR
     269-461: Missing.

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view
Molecule processing
	Signal peptide	1 – 22	22
	Chain	23 – 461	439	Tumor necrosis factor receptor superfamily member 1b, membrane form
	Chain	27 – ?		Tumor necrosis factor-binding protein 2
Regions
	Topological domain	23 – 257	235	Extracellular Potential
	Transmembrane	258 – 287	30	Potential
	Topological domain	288 – 461	174	Cytoplasmic Potential
	Repeat	39 – 76	38	TNFR-Cys 1
	Repeat	77 – 118	42	TNFR-Cys 2
	Repeat	119 – 162	44	TNFR-Cys 3
	Repeat	163 – 201	39	TNFR-Cys 4
Amino acid modifications
	Glycosylation	171	1	N-linked (GlcNAc...) Potential
	Glycosylation	193	1	N-linked (GlcNAc...) Potential
	Disulfide bond	40 ↔ 53		By similarity
	Disulfide bond	54 ↔ 67		By similarity
	Disulfide bond	57 ↔ 75		By similarity
	Disulfide bond	78 ↔ 93		By similarity
	Disulfide bond	96 ↔ 110		By similarity
	Disulfide bond	100 ↔ 118		By similarity
	Disulfide bond	120 ↔ 126		By similarity
	Disulfide bond	134 ↔ 143		By similarity
	Disulfide bond	137 ↔ 161		By similarity
	Disulfide bond	164 ↔ 179		By similarity
Natural variations
	Alternative sequence	263 – 268	6	GLIVGV → ASLACR in isoform 2.
	Alternative sequence	269 – 461	193	Missing in isoform 2.
	Natural variant	187	1	V → M: dbSNP rs2228494.
	Natural variant	196	1	M → R Frequent polymorphism; seems to be associated with hyperandrogenism, polycystic ovary syndrome (PCOS) and systemic lupus erythematosus. dbSNP rs1061622.
	Natural variant	232	1	E → K: dbSNP rs5746026.
	Natural variant	236	1	A → T: dbSNP rs5746027.
	Natural variant	264	1	L → P: dbSNP rs2229700.
	Natural variant	269	1	T → P: dbSNP rs17879042.
	Natural variant	295	1	Q → R: dbSNP rs5746032.
	Natural variant	301	1	P → R: dbSNP rs17883432.
Experimental info
	Sequence conflict	98	1	S → P in AAN72434. Ref.4
	Sequence conflict	102	1	S → P in AAN72434. Ref.4
	Sequence conflict	141	1	R → P in AAA63262. Ref.11
	Sequence conflict	363	1	A → T in AAA63262. Ref.11

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 [UniParc]. Last modified May 27, 2002. Version 3. Checksum: 603D0AE1CD69ACBF	FASTA	461	48,291
	10 20 30 40 50 60 MAPVAVWAAL AVGLELWAAA HALPAQVAFT PYAPEPGSTC RLREYYDQTA QMCCSKCSPG 70 80 90 100 110 120 QHAKVFCTKT SDTVCDSCED STYTQLWNWV PECLSCGSRC SSDQVETQAC TREQNRICTC 130 140 150 160 170 180 RPGWYCALSK QEGCRLCAPL RKCRPGFGVA RPGTETSDVV CKPCAPGTFS NTTSSTDICR 190 200 210 220 230 240 PHQICNVVAI PGNASMDAVC TSTSPTRSMA PGAVHLPQPV STRSQHTQPT PEPSTAPSTS 250 260 270 280 290 300 FLLPMGPSPP AEGSTGDFAL PVGLIVGVTA LGLLIIGVVN CVIMTQVKKK PLCLQREAKV 310 320 330 340 350 360 PHLPADKARG TQGPEQQHLL ITAPSSSSSS LESSASALDR RAPTRNQPQA PGVEASGAGE 370 380 390 400 410 420 ARASTGSSDS SPGGHGTQVN VTCIVNVCSS SDHSSQCSSQ ASSTMGDTDS SPSESPKDEQ 430 440 450 460 VPFSKEECAF RSQLETPETL LGSTEEKPLP LGVPDAGMKP S
	Isoform 2 (DS-TNFR2(Delta7,8)) (sTNFR2) [UniParc]. Checksum: 51A97BA5222FA444		268	28,461
	10 20 30 40 50 60 MAPVAVWAAL AVGLELWAAA HALPAQVAFT PYAPEPGSTC RLREYYDQTA QMCCSKCSPG 70 80 90 100 110 120 QHAKVFCTKT SDTVCDSCED STYTQLWNWV PECLSCGSRC SSDQVETQAC TREQNRICTC 130 140 150 160 170 180 RPGWYCALSK QEGCRLCAPL RKCRPGFGVA RPGTETSDVV CKPCAPGTFS NTTSSTDICR 190 200 210 220 230 240 PHQICNVVAI PGNASMDAVC TSTSPTRSMA PGAVHLPQPV STRSQHTQPT PEPSTAPSTS 250 260 FLLPMGPSPP AEGSTGDFAL PVASLACR

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"A receptor for tumor necrosis factor defines an unusual family of cellular and viral proteins." Smith C.A., Davis T., Anderson D., Solam L., Beckmann M.P., Jerzy R., Dower S.K., Cosman D., Goodwin R.G. Science 248:1019-1023(1990) [PubMed: 2160731] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
[2]	"A second tumor necrosis factor receptor gene product can shed a naturally occurring tumor necrosis factor inhibitor." Kohno T., Brewer M.T., Baker S.L., Schwartz P.E., King M.W., Hale K.K., Squires C.H., Thompson R.C., Vannice J.L. Proc. Natl. Acad. Sci. U.S.A. 87:8331-8335(1990) [PubMed: 2172983] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), VARIANT ARG-196.
[3]	"Physical mapping and genomic structure of the human TNFR2 gene." Beltinger C.P., White P.S., Maris J.M., Sulman E.P., Jensen S.J., Lepaslier D., Stallard B.J., Goeddel D.V., Desauvage F.J., Brodeur G.M. Genomics 35:94-100(1996) [PubMed: 8661109] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] (ISOFORM 1).
[4]	"Identification and characterization of a novel spliced variant that encodes human soluble tumor necrosis factor receptor 2." Lainez B., Fernandez-Real J.M., Romero X., Esplugues E., Canete J.D., Ricart W., Engel P. Int. Immunol. 16:169-177(2004) [PubMed: 14688072] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2), SUBCELLULAR LOCATION, FUNCTION OF ISOFORM 2.
[5]	"Cloning of human full-length CDSs in BD Creator(TM) system donor vector." Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S., Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y., Phelan M., Farmer A. Submitted (OCT-2004) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
[6]	NIEHS SNPs program Submitted (MAR-2003) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA], VARIANTS MET-187; ARG-196; LYS-232; THR-236; PRO-264 AND ARG-295.
[7]	SeattleSNPs program for genomic applications Submitted (JUL-2003) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA], VARIANTS ARG-196; LYS-232; PRO-269 AND ARG-301.
[8]	"The DNA sequence and biological annotation of human chromosome 1." Gregory S.G., Barlow K.F., McLay K.E., Kaul R., Swarbreck D., Dunham A., Scott C.E., Howe K.L., Woodfine K., Spencer C.C.A., Jones M.C., Gillson C., Searle S., Zhou Y., Kokocinski F., McDonald L., Evans R., Phillips K. , Atkinson A., Cooper R., Jones C., Hall R.E., Andrews T.D., Lloyd C., Ainscough R., Almeida J.P., Ambrose K.D., Anderson F., Andrew R.W., Ashwell R.I.S., Aubin K., Babbage A.K., Bagguley C.L., Bailey J., Beasley H., Bethel G., Bird C.P., Bray-Allen S., Brown J.Y., Brown A.J., Buckley D., Burton J., Bye J., Carder C., Chapman J.C., Clark S.Y., Clarke G., Clee C., Cobley V., Collier R.E., Corby N., Coville G.J., Davies J., Deadman R., Dunn M., Earthrowl M., Ellington A.G., Errington H., Frankish A., Frankland J., French L., Garner P., Garnett J., Gay L., Ghori M.R.J., Gibson R., Gilby L.M., Gillett W., Glithero R.J., Grafham D.V., Griffiths C., Griffiths-Jones S., Grocock R., Hammond S., Harrison E.S.I., Hart E., Haugen E., Heath P.D., Holmes S., Holt K., Howden P.J., Hunt A.R., Hunt S.E., Hunter G., Isherwood J., James R., Johnson C., Johnson D., Joy A., Kay M., Kershaw J.K., Kibukawa M., Kimberley A.M., King A., Knights A.J., Lad H., Laird G., Lawlor S., Leongamornlert D.A., Lloyd D.M., Loveland J., Lovell J., Lush M.J., Lyne R., Martin S., Mashreghi-Mohammadi M., Matthews L., Matthews N.S.W., McLaren S., Milne S., Mistry S., Moore M.J.F., Nickerson T., O'Dell C.N., Oliver K., Palmeiri A., Palmer S.A., Parker A., Patel D., Pearce A.V., Peck A.I., Pelan S., Phelps K., Phillimore B.J., Plumb R., Rajan J., Raymond C., Rouse G., Saenphimmachak C., Sehra H.K., Sheridan E., Shownkeen R., Sims S., Skuce C.D., Smith M., Steward C., Subramanian S., Sycamore N., Tracey A., Tromans A., Van Helmond Z., Wall M., Wallis J.M., White S., Whitehead S.L., Wilkinson J.E., Willey D.L., Williams H., Wilming L., Wray P.W., Wu Z., Coulson A., Vaudin M., Sulston J.E., Durbin R.M., Hubbard T., Wooster R., Dunham I., Carter N.P., McVean G., Ross M.T., Harrow J., Olson M.V., Beck S., Rogers J., Bentley D.R. Nature 441:315-321(2006) [PubMed: 16710414] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[9]	"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)." The MGC Project Team Genome Res. 14:2121-2127(2004) [PubMed: 15489334] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). Tissue: PNS.
[10]	"Two human TNF receptors have similar extracellular, but distinct intracellular, domain sequences." Dembic Z., Loetscher H., Gubler U., Pan Y.C., Lahm H.-W., Gentz R., Brockhaus M., Lesslauer W. Cytokine 2:231-237(1990) [PubMed: 1966549] [Abstract] Cited for: NUCLEOTIDE SEQUENCE OF 37-461 (ISOFORM 1).
[11]	"Complementary DNA cloning of a receptor for tumor necrosis factor and demonstration of a shed form of the receptor." Heller R.A., Song K., Onasch M.A., Fischer W.H., Chang D., Ringold G.M. Proc. Natl. Acad. Sci. U.S.A. 87:6151-6155(1990) [PubMed: 2166946] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 116-461 (ISOFORM 1), PARTIAL PROTEIN SEQUENCE, VARIANT ARG-196.
[12]	"New single nucleotide polymorphisms in the coding region of human TNFR2: association with systemic lupus erythematosus." Tsuchiya N., Komata T., Matsushita M., Ohashi J., Tokunaga K. Genes Immun. 1:501-503(2000) [PubMed: 11197692] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 154-183, VARIANTS ARG-196 AND LYS-232.
[13]	"Two tumor necrosis factor-binding proteins purified from human urine. Evidence for immunological cross-reactivity with cell surface tumor necrosis factor receptors." Engelmann H., Novick D., Wallach D. J. Biol. Chem. 265:1531-1536(1990) [PubMed: 2153136] [Abstract] Cited for: PROTEIN SEQUENCE OF 27-31. Tissue: Urine.
[14]	"Purification and partial amino acid sequence analysis of two distinct tumor necrosis factor receptors from HL60 cells." Loetscher H., Schlaeger E.J., Lahm H.-W., Pan Y.-C.E., Lesslauer W., Brockhaus M. J. Biol. Chem. 265:20131-20138(1990) [PubMed: 2173696] [Abstract] Cited for: PROTEIN SEQUENCE OF 23-40; 65-69; 136-141; 300-306 AND 346-362.
[15]	"Biochemical properties of the 75-kDa tumor necrosis factor receptor. Characterization of ligand binding, internalization, and receptor phosphorylation." Pennica D., Lam V.T., Mize N.K., Weber R.F., Lewis M., Fendly B.M., Lipari M.T., Goeddel D.V. J. Biol. Chem. 267:21172-21178(1992) [PubMed: 1328224] [Abstract] Cited for: CHARACTERIZATION.
[16]	"A novel family of putative signal transducers associated with the cytoplasmic domain of the 75 kDa tumor necrosis factor receptor." Rothe M., Wong S.C., Henzel W.J., Goeddel D.V. Cell 78:681-692(1994) [PubMed: 8069916] [Abstract] Cited for: INTERACTION WITH TRAF2.
[17]	"Structural basis for self-association and receptor recognition of human TRAF2." Park Y.C., Burkitt V., Villa A.R., Tong L., Wu H. Nature 398:533-538(1999) [PubMed: 10206649] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.3 ANGSTROMS) OF 419-428 IN COMPLEX WITH TRAF2.
[18]	"Association of tumor necrosis factor receptor type II polymorphism 196R with systemic lupus erythematosus in the Japanese: molecular and functional analysis." Morita C., Horiuchi T., Tsukamoto H., Hatta N., Kikuchi Y., Arinobu Y., Otsuka T., Sawabe T., Harashima S., Nagasawa K., Niho Y. Arthritis Rheum. 44:2819-2827(2001) [PubMed: 11762942] [Abstract] Cited for: VARIANTS ARG-196 AND LYS-232.
[19]	"Comment: the methionine 196 arginine polymorphism in exon 6 of the TNF receptor 2 gene (TNFRSF1B) is associated with the polycystic ovary syndrome and hyperandrogenism." Peral B., San Millan J.L., Castello R., Moghetti P., Escobar-Morreale H.F. J. Clin. Endocrinol. Metab. 87:3977-3983(2002) [PubMed: 12161545] [Abstract] Cited for: VARIANT ARG-196.
+	Additional computationally mapped references.

Web resources

SeattleSNPs

NIEHS SNPs

Enbrel

Clinical information on Enbrel

Cross-references

Sequence databases

EMBLGenBankDDBJ

M32315 mRNA. Translation: AAA59929.1.
U52165 , U52156, U52157, U52158, U52159, U52160, U52161, U52162, U52163, U52164 Genomic DNA. Translation: AAC50622.1.
M55994 mRNA. Translation: AAA36755.1.
AY148473 mRNA. Translation: AAN72434.1.
BT019927 mRNA. Translation: AAV38730.1.
AY264804 Genomic DNA. Translation: AAO89076.1.
AY342040 Genomic DNA. Translation: AAP88939.1.
AL357835, AL031276 Genomic DNA. Translation: CAH73721.1.
BC052977 mRNA. Translation: AAH52977.1.
S63368 mRNA. Translation: AAB19824.2.
M35857 mRNA. Translation: AAA63262.1.
AB030950 Genomic DNA. Translation: BAA89053.1.

PIR

A35356.

RefSeq

NP_001057.1.

UniGene

Hs.256278

3D structure databases

PDBMSD

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
1CA9	X-ray	2.30	G/H	420-428	[»]

ModBase

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Protein-protein interaction databases

DIP