P01374 (TNFB_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Lymphotoxin-alpha
Short name=LT-alpha

Alternative name(s):
TNF-beta
Tumor necrosis factor ligand superfamily member 1

Gene names

Name:	LTA
Synonyms:	TNFB, TNFSF1

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	205 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	Cytokine that in its homotrimeric form binds to TNFRSF1A/TNFR1, TNFRSF1B/TNFBR and TNFRSF14/HVEM. In its heterotrimeric form with LTB binds to TNFRSF3/LTBR. Lymphotoxin is produced by lymphocytes and cytotoxic for a wide range of tumor cells in vitro and in vivo.
Subunit structure	Homotrimer, and heterotrimer of either two LTB and one LTA subunits or (less prevalent) two LTA and one LTB subunits.
Subcellular location	Secreted. Membrane. Note: The homotrimer is secreted. The heterotrimer is membrane-associated.
Polymorphism	A polymorphism in LTA accounts, in part, for susceptibility to leprosy linked to chromosome 6p21.3 (LPRS4) [MIM:610988].
Involvement in disease	Psoriatic arthritis (PSORAS) [MIM:607507]: An inflammatory, seronegative arthritis associated with psoriasis. It is a heterogeneous disorder ranging from a mild, non-destructive disease to a severe, progressive, erosive arthropathy. Five types of psoriatic arthritis have been defined: asymmetrical oligoarthritis characterized by primary involvement of the small joints of the fingers or toes; asymmetrical arthritis which involves the joints of the extremities; symmetrical polyarthritis characterized by a rheumatoidlike pattern that can involve hands, wrists, ankles, and feet; arthritis mutilans, which is a rare but deforming and destructive condition; arthritis of the sacroiliac joints and spine (psoriatic spondylitis). Note: Disease susceptibility is associated with variations affecting the gene represented in this entry.
Sequence similarities	Belongs to the tumor necrosis factor family.

Ontologies

Keywords
Cellular component	Membrane Secreted
Coding sequence diversity	Polymorphism
Domain	Signal
Molecular function	Cytokine
PTM	Glycoprotein
Technical term	3D-structure Complete proteome Direct protein sequencing Reference proteome
Gene Ontology (GO)
Biological_process	cell-cell signaling Traceable author statement Ref.4. Source: ProtInc defense response to Gram-positive bacterium Inferred from electronic annotation. Source: Compara humoral immune response Inferred from electronic annotation. Source: Compara induction of apoptosis Traceable author statement Ref.4. Source: ProtInc lymph node development Inferred from electronic annotation. Source: Compara negative regulation of fibroblast proliferation Inferred from electronic annotation. Source: Compara negative regulation of growth of symbiont in host Inferred from electronic annotation. Source: Compara positive regulation of chronic inflammatory response to antigenic stimulus Inferred from electronic annotation. Source: Compara positive regulation of humoral immune response mediated by circulating immunoglobulin Inferred from electronic annotation. Source: Compara positive regulation of interferon-gamma production Inferred from electronic annotation. Source: Compara response to drug Inferred from electronic annotation. Source: Compara response to hypoxia Inferred from electronic annotation. Source: Compara response to lipopolysaccharide Inferred from electronic annotation. Source: Compara response to nutrient Inferred from electronic annotation. Source: Compara signal transduction Traceable author statement Ref.4. Source: ProtInc
Cellular_component	extracellular space Inferred from electronic annotation. Source: UniProtKB-KW membrane Inferred from electronic annotation. Source: UniProtKB-SubCell
Molecular_function	receptor binding Traceable author statement PubMed 3001529. Source: ProtInc
Complete GO annotation...

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Signal peptide

1 – 34

34

Chain

35 – 205

171

Lymphotoxin-alpha

PRO_0000034463

Amino acid modifications

Glycosylation

41

1

O-linked (GalNAc...); partial Ref.13

Glycosylation

96

1

N-linked (GlcNAc...) Ref.13

CAR_000048

Natural variations

Natural variant

13

1

C → R. Ref.10 Ref.11 Ref.12
Corresponds to variant rs2229094 [ dbSNP | Ensembl ].

VAR_013023

Natural variant

51

1

H → P. Ref.10 Ref.11
Corresponds to variant rs2229092 [ dbSNP | Ensembl ].

VAR_013024

Natural variant

60

1

T → N in allele TNFB*2. Ref.10 Ref.11 Ref.13 Ref.16
Corresponds to variant rs1041981 [ dbSNP | Ensembl ].

VAR_007511

Natural variant

125

1

T → P in allele 8.1. Ref.17

VAR_007512

Secondary structure

1

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205

Helix Strand Turn

Details...

Beta strand

64 – 69

6

Beta strand

74 – 76

3

Beta strand

87 – 89

3

Beta strand

93 – 95

3

Beta strand

98 – 100

3

Beta strand

103 – 117

15

Helix

122 – 125

4

Beta strand

129 – 138

10

Beta strand

142 – 144

3

Beta strand

146 – 155

10

Beta strand

163 – 175

13

Beta strand

180 – 186

7

Helix

188 – 190

3

Turn

195 – 197

3

Beta strand

198 – 204

7

Sequences

	Sequence		Length	Mass (Da)
	P01374 [UniParc]. Last modified July 1, 1989. Version 2. Checksum: 1BBD5E7D496A3A82	FASTA	205	22,297
	10 20 30 40 50 60 MTPPERLFLP RVCGTTLHLL LLGLLLVLLP GAQGLPGVGL TPSAAQTARQ HPKMHLAHST 70 80 90 100 110 120 LKPAAHLIGD PSKQNSLLWR ANTDRAFLQD GFSLSNNSLL VPTSGIYFVY SQVVFSGKAY 130 140 150 160 170 180 SPKATSSPLY LAHEVQLFSS QYPFHVPLLS SQKMVYPGLQ EPWLHSMYHG AAFQLTQGDQ 190 200 LSTHTDGIPH LVLSPSTVFF GAFAL

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Tandem arrangement of genes coding for tumor necrosis factor (TNF-alpha) and lymphotoxin (TNF-beta) in the human genome." Nedospasov S.A., Shakhov A.N., Turetskaya R.L., Mett V.A., Azizov M.M., Georgiev G.P., Korobko V.G., Dobrynin V.N., Filippov S.A., Bystrov N.S., Boldyreva E.F., Chuvpilo S.A., Chumakov A.M., Shingarova L.N., Ovchinnikov Y.A. Cold Spring Harb. Symp. Quant. Biol. 51:611-624(1986) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[2]	"Structure and chromosomal localization of the human lymphotoxin gene." Nedwin G.E., Jarrett-Nedwin J., Smith D.H., Naylor S.L., Sakaguchi A.Y., Goeddel D.V., Gray P.W. J. Cell. Biochem. 29:171-181(1985) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[3]	"Cloning and expression of human lymphotoxin mRNA derived from a human T cell hybridoma." Kobayashi Y., Miyamoto D., Asada M., Obinata M., Osawa T. J. Biochem. 100:727-733(1986) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[4]	"Cloning and expression of cDNA for human lymphotoxin, a lymphokine with tumour necrosis activity." Gray P.W., Aggarwal B.B., Benton C.V., Bringman T.S., Henzel W.J., Jarrett J.A., Leung D.W., Moffat B., Ng P., Svedersky L.P., Palladino M.A., Nedwin G.E. Nature 312:721-724(1984) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[5]	"Nucleotide sequence of a cDNA encoding human tumor necrosis factor beta from B lymphoblastoid cell RPMI 1788." Matsuyama N., Okawa N., Tsukii Y., Endo T., Kaji A. FEBS Lett. 302:141-144(1992) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[6]	"Dense Alu clustering and a potential new member of the NF kappa B family within a 90 kilobase HLA class III segment." Iris F.J.M., Bougueleret L., Prieur S., Caterina D., Primas G., Perrot V., Jurka J., Rodriguez-Tome P., Claverie J.-M., Dausset J., Cohen D. Nat. Genet. 3:137-145(1993) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[7]	"A new member of the Ig superfamily and a V-ATPase G subunit are among the predicted products of novel genes close to the TNF locus in the human MHC." Neville M.J., Campbell R.D. J. Immunol. 162:4745-4754(1999) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[8]	"Analysis of the gene-dense major histocompatibility complex class III region and its comparison to mouse." Xie T., Rowen L., Aguado B., Ahearn M.E., Madan A., Qin S., Campbell R.D., Hood L. Genome Res. 13:2621-2636(2003) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[9]	"Homo sapiens 2,229,817bp genomic DNA of 6p21.3 HLA class I region." Shiina S., Tamiya G., Oka A., Inoko H. Submitted (SEP-1999) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[10]	SeattleSNPs variation discovery resource Submitted (DEC-2001) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA], VARIANTS ARG-13; PRO-51 AND ASN-60.
[11]	NIEHS SNPs program Submitted (JAN-2003) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA], VARIANTS ARG-13; PRO-51 AND ASN-60.
[12]	"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] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], VARIANT ARG-13. Tissue: Lymph.
[13]	"Natural human tumor necrosis factor beta (lymphotoxin). Variable O-glycosylation at Thr7, proteolytic processing, and allelic variation." Voigt C.G., Maurer-Fogy I., Adolf G.R. FEBS Lett. 314:85-88(1992) [PubMed] [Europe PMC] [Abstract] Cited for: PARTIAL PROTEIN SEQUENCE, GLYCOSYLATION AT THR-41 AND ASN-96, VARIANT ASN-60.
[14]	"The structure of human lymphotoxin (tumor necrosis factor-beta) at 1.9-A resolution." Eck M.J., Ultsch M., Rinderknecht E., de Vos A.M., Sprang S.R. J. Biol. Chem. 267:2119-2122(1992) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (1.9 ANGSTROMS).
[15]	"Crystal structure of the soluble human 55 kd TNF receptor-human TNF beta complex: implications for TNF receptor activation." Banner D.W., D'Arcy A., Janes W., Gentz R., Schoenfeld H.-J., Broger C., Loetscher H., Lesslauer W. Cell 73:431-445(1993) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.85 ANGSTROMS) OF 61-205 OF COMPLEX WITH TNFR1.
[16]	"Polymorphic structure of the tumor necrosis factor (TNF) locus: an NcoI polymorphism in the first intron of the human TNF-beta gene correlates with a variant amino acid in position 26 and a reduced level of TNF-beta production." Messer G., Spengler U., Jung M.C., Honold G., Bloemer K., Pape G.R., Riethmueller G., Weiss E.H. J. Exp. Med. 173:209-219(1991) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANT ASN-60.
[17]	"Haplotypic polymorphisms of the TNFB gene." Abraham L.J., Du D.C., Zahedi K., Dawkins R.L., Whitehead A.S. Immunogenetics 33:50-53(1991) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANT PRO-125.
[18]	"Cytokine gene polymorphisms: association with psoriatic arthritis susceptibility and severity." Balding J., Kane D., Livingstone W., Mynett-Johnson L., Bresnihan B., Smith O., FitzGerald O. Arthritis Rheum. 48:1408-1413(2003) [PubMed] [Europe PMC] [Abstract] Cited for: INVOLVEMENT IN PSORIATIC ARTHRITIS SUSCEPTIBILITY.
[19]	"Stepwise replication identifies a low-producing lymphotoxin-alpha allele as a major risk factor for early-onset leprosy." Alcaies A., Alter A., Antoni G., Orlova M., Nguyen V.T., Singh M., Vanderborght P.R., Katoch K., Mira M.T., Vu H.T., Ngyuen T.H., Nguyen N.B., Moraes M., Mehra N., Schurr E., Abel L. Nat. Genet. 39:517-522(2007) [PubMed] [Europe PMC] [Abstract] Cited for: INVOLVEMENT IN LPRS4.
+	Additional computationally mapped references.

Web resources

Wikipedia

Lymphotoxin entry

Atlas of Genetics and Cytogenetics in Oncology and Haematology

NIEHS-SNPs

SeattleSNPs

SHMPD

The Singapore human mutation and polymorphism database

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

X01393 mRNA. Translation: CAA25649.1.
X02911 Genomic DNA. Translation: CAA26670.1.
D00102 mRNA. Translation: BAA00064.1.
M16441 Genomic DNA. Translation: AAA61199.1.
D12614 mRNA. Translation: BAA02139.1.
M55913 Genomic DNA. Translation: AAB59455.1.
Z15026 Genomic DNA. Translation: CAA78746.1.
Y14768 Genomic DNA. Translation: CAA75071.1.
AF129756 Genomic DNA. Translation: AAD18092.1.
BA000025 Genomic DNA. Translation: BAB63397.1.
AY070490 Genomic DNA. Translation: AAL49956.1.
AY216498 Genomic DNA. Translation: AAO21135.1.
BC034729 mRNA. Translation: AAH34729.1.

IPI

IPI00001670.

PIR

QWHUX. A92755.

RefSeq

NP_000586.2. NM_000595.3.
NP_001153212.1. NM_001159740.2.

UniGene

Hs.36.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
1TNR	X-ray	2.85	A	62-205	[»]

ProteinModelPortal

P01374.

ModBase

Search...

Protein-protein interaction databases

DIP

DIP-2910N.
DIP-6228N.

IntAct

P01374. 1 interaction.

MINT

MINT-365276.

STRING

9606.ENSP00000372793.

PTM databases

GlycoSuiteDB

P01374.

Polymorphism databases

DMDM

135940.

Proteomic databases

PRIDE

P01374.

Protocols and materials databases

DNASU

4049.

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000412851; ENSP00000412555; ENSG00000230279.
ENST00000418386; ENSP00000413450; ENSG00000226979.
ENST00000426845; ENSP00000402413; ENSG00000230279.
ENST00000436519; ENSP00000395976; ENSG00000231408.
ENST00000454550; ENSP00000416509; ENSG00000231408.
ENST00000454783; ENSP00000403495; ENSG00000226979.

GeneID

4049.

KEGG

hsa:4049.

UCSC

uc003nue.1. human.

Organism-specific databases

CTD

4049.

GeneCards

GC06P031541.

HGNC

HGNC:6709. LTA.

HPA

HPA007729.

MIM

153440. gene.
607507. phenotype.
610988. phenotype.

neXtProt

NX_P01374.

Orphanet

40050. Adult psoriatic arthritis.

PharmGKB

PA30474.

GenAtlas

Search...

Phylogenomic databases

eggNOG

NOG41746.

HOGENOM

HOG000048729.

HOVERGEN

HBG012516.

InParanoid

P01374.

KO

K05468.

OMA

QGPWVRS.

OrthoDB

EOG40P47W.

PhylomeDB

P01374.

Enzyme and pathway databases

Pathway_Interaction_DB

il2_stat5pathway. IL2 signaling events mediated by STAT5.
il4_2pathway. IL4-mediated signaling events.

Gene expression databases

ArrayExpress

P01374.

Bgee

P01374.

CleanEx

HS_LTA.

Genevestigator

P01374.

GermOnline

ENSG00000204496. Homo sapiens.

Family and domain databases

Gene3D

2.60.120.40. 1 hit.

InterPro

IPR006052. TNF.
IPR006053. TNF_a/b/c.
IPR002960. TNF_beta.
IPR021184. TNF_CS.
IPR008983. Tumour_necrosis_fac-like_dom.
[Graphical view]

Pfam

PF00229. TNF. 1 hit.
[Graphical view]

PRINTS

PR01234. TNECROSISFCT.
PR01236. TNFBETA.

SMART

SM00207. TNF. 1 hit.
[Graphical view]

SUPFAM

SSF49842. TNF_like. 1 hit.

PROSITE

PS00251. TNF_1. 1 hit.
PS50049. TNF_2. 1 hit.
[Graphical view]

ProtoNet

Search...

Other

BindingDB

P01374.

ChEMBL

CHEMBL2059.

DrugBank

DB00005. Etanercept.

EvolutionaryTrace

P01374.

GenomeRNAi

4049.

NextBio

15860.

SOURCE

Search...

Entry information

Entry name

TNFB_HUMAN

Accession

Primary (citable) accession number: P01374
Secondary accession number(s): Q8N4C3, Q9UKS8

Entry history

Integrated into UniProtKB/Swiss-Prot:	July 21, 1986
Last sequence update:	July 1, 1989
Last modified:	May 1, 2013
This is version 154 of the entry and version 2 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.