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Lymphotoxin-alpha (LT-alpha) (TNF-beta) (Tumor necrosis factor ligand superfamily member 1)

 TNFB_HUMAN              Reviewed;         205 AA.
P01374; Q8N4C3; Q9UKS8;
21-JUL-1986, integrated into UniProtKB/Swiss-Prot.
01-JUL-1989, sequence version 2.
23-MAY-2018, entry version 193.
RecName: Full=Lymphotoxin-alpha;
Short=LT-alpha;
AltName: Full=TNF-beta;
AltName: Full=Tumor necrosis factor ligand superfamily member 1;
Flags: Precursor;
Name=LTA; Synonyms=TNFB, TNFSF1;
Homo sapiens (Human).
Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
Catarrhini; Hominidae; Homo.
NCBI_TaxID=9606;
[1]
NUCLEOTIDE SEQUENCE [GENOMIC DNA].
PubMed=3555974;
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.;
"Tandem arrangement of genes coding for tumor necrosis factor (TNF-
alpha) and lymphotoxin (TNF-beta) in the human genome.";
Cold Spring Harb. Symp. Quant. Biol. 51:611-624(1986).
[2]
NUCLEOTIDE SEQUENCE [GENOMIC DNA].
PubMed=3001109; DOI=10.1002/jcb.240290302;
Nedwin G.E., Jarrett-Nedwin J., Smith D.H., Naylor S.L.,
Sakaguchi A.Y., Goeddel D.V., Gray P.W.;
"Structure and chromosomal localization of the human lymphotoxin
gene.";
J. Cell. Biochem. 29:171-181(1985).
[3]
NUCLEOTIDE SEQUENCE [MRNA].
PubMed=3536896;
Kobayashi Y., Miyamoto D., Asada M., Obinata M., Osawa T.;
"Cloning and expression of human lymphotoxin mRNA derived from a human
T cell hybridoma.";
J. Biochem. 100:727-733(1986).
[4]
NUCLEOTIDE SEQUENCE [MRNA].
PubMed=6334807; DOI=10.1038/312721a0;
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.;
"Cloning and expression of cDNA for human lymphotoxin, a lymphokine
with tumour necrosis activity.";
Nature 312:721-724(1984).
[5]
NUCLEOTIDE SEQUENCE [MRNA].
PubMed=1353024; DOI=10.1016/0014-5793(92)80425-G;
Matsuyama N., Okawa N., Tsukii Y., Endo T., Kaji A.;
"Nucleotide sequence of a cDNA encoding human tumor necrosis factor
beta from B lymphoblastoid cell RPMI 1788.";
FEBS Lett. 302:141-144(1992).
[6]
NUCLEOTIDE SEQUENCE [GENOMIC DNA].
PubMed=8499947; DOI=10.1038/ng0293-137;
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.;
"Dense Alu clustering and a potential new member of the NF kappa B
family within a 90 kilobase HLA class III segment.";
Nat. Genet. 3:137-145(1993).
[7]
NUCLEOTIDE SEQUENCE [GENOMIC DNA].
PubMed=10202016;
Neville M.J., Campbell R.D.;
"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.";
J. Immunol. 162:4745-4754(1999).
[8]
NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
PubMed=14656967; DOI=10.1101/gr.1736803;
Xie T., Rowen L., Aguado B., Ahearn M.E., Madan A., Qin S.,
Campbell R.D., Hood L.;
"Analysis of the gene-dense major histocompatibility complex class III
region and its comparison to mouse.";
Genome Res. 13:2621-2636(2003).
[9]
NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
Shiina S., Tamiya G., Oka A., Inoko H.;
"Homo sapiens 2,229,817bp genomic DNA of 6p21.3 HLA class I region.";
Submitted (SEP-1999) to the EMBL/GenBank/DDBJ databases.
[10]
NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANTS ARG-13; PRO-51 AND
ASN-60.
SeattleSNPs variation discovery resource;
Submitted (DEC-2001) to the EMBL/GenBank/DDBJ databases.
[11]
NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANTS ARG-13; PRO-51 AND
ASN-60.
NIEHS SNPs program;
Submitted (JAN-2003) to the EMBL/GenBank/DDBJ databases.
[12]
NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], AND VARIANT ARG-13.
TISSUE=Lymph;
PubMed=15489334; DOI=10.1101/gr.2596504;
The MGC Project Team;
"The status, quality, and expansion of the NIH full-length cDNA
project: the Mammalian Gene Collection (MGC).";
Genome Res. 14:2121-2127(2004).
[13]
PARTIAL PROTEIN SEQUENCE, GLYCOSYLATION AT THR-41 AND ASN-96, AND
VARIANT ASN-60.
PubMed=1451807; DOI=10.1016/0014-5793(92)81467-Z;
Voigt C.G., Maurer-Fogy I., Adolf G.R.;
"Natural human tumor necrosis factor beta (lymphotoxin). Variable O-
glycosylation at Thr7, proteolytic processing, and allelic
variation.";
FEBS Lett. 314:85-88(1992).
[14]
X-RAY CRYSTALLOGRAPHY (1.9 ANGSTROMS).
PubMed=1733919;
Eck M.J., Ultsch M., Rinderknecht E., de Vos A.M., Sprang S.R.;
"The structure of human lymphotoxin (tumor necrosis factor-beta) at
1.9-A resolution.";
J. Biol. Chem. 267:2119-2122(1992).
[15]
X-RAY CRYSTALLOGRAPHY (2.85 ANGSTROMS) OF 61-205 OF COMPLEX WITH
TNFR1.
PubMed=8387891; DOI=10.1016/0092-8674(93)90132-A;
Banner D.W., D'Arcy A., Janes W., Gentz R., Schoenfeld H.-J.,
Broger C., Loetscher H., Lesslauer W.;
"Crystal structure of the soluble human 55 kd TNF receptor-human TNF
beta complex: implications for TNF receptor activation.";
Cell 73:431-445(1993).
[16]
VARIANT ASN-60.
PubMed=1670638; DOI=10.1084/jem.173.1.209;
Messer G., Spengler U., Jung M.C., Honold G., Bloemer K., Pape G.R.,
Riethmueller G., Weiss E.H.;
"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.";
J. Exp. Med. 173:209-219(1991).
[17]
VARIANT PRO-125.
PubMed=1671667; DOI=10.1007/BF00211695;
Abraham L.J., Du D.C., Zahedi K., Dawkins R.L., Whitehead A.S.;
"Haplotypic polymorphisms of the TNFB gene.";
Immunogenetics 33:50-53(1991).
[18]
INVOLVEMENT IN PSORIATIC ARTHRITIS SUSCEPTIBILITY.
PubMed=12746914; DOI=10.1002/art.10935;
Balding J., Kane D., Livingstone W., Mynett-Johnson L., Bresnihan B.,
Smith O., FitzGerald O.;
"Cytokine gene polymorphisms: association with psoriatic arthritis
susceptibility and severity.";
Arthritis Rheum. 48:1408-1413(2003).
[19]
INVOLVEMENT IN LPRS4.
PubMed=17353895; DOI=10.1038/ng2000;
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.;
"Stepwise replication identifies a low-producing lymphotoxin-alpha
allele as a major risk factor for early-onset leprosy.";
Nat. Genet. 39:517-522(2007).
-!- 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: 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].
-!- 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 rheumatoid like 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).
{ECO:0000269|PubMed:12746914}. Note=Disease susceptibility is
associated with variations affecting the gene represented in this
entry.
-!- SIMILARITY: Belongs to the tumor necrosis factor family.
{ECO:0000305}.
-!- WEB RESOURCE: Name=Wikipedia; Note=Lymphotoxin entry;
URL="https://en.wikipedia.org/wiki/Lymphotoxin";
-!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology
and Haematology;
URL="http://atlasgeneticsoncology.org/Genes/LTAID41209ch6p21.html";
-!- WEB RESOURCE: Name=NIEHS-SNPs;
URL="http://egp.gs.washington.edu/data/lta/";
-!- WEB RESOURCE: Name=SeattleSNPs;
URL="http://pga.gs.washington.edu/data/lta/";
-!- WEB RESOURCE: Name=SHMPD; Note=The Singapore human mutation and
polymorphism database;
URL="http://shmpd.bii.a-star.edu.sg/gene.php?genestart=A&genename=LTA";
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EMBL; X01393; CAA25649.1; -; mRNA.
EMBL; X02911; CAA26670.1; -; Genomic_DNA.
EMBL; D00102; BAA00064.1; -; mRNA.
EMBL; M16441; AAA61199.1; -; Genomic_DNA.
EMBL; D12614; BAA02139.1; -; mRNA.
EMBL; M55913; AAB59455.1; -; Genomic_DNA.
EMBL; Z15026; CAA78746.1; -; Genomic_DNA.
EMBL; Y14768; CAA75071.1; -; Genomic_DNA.
EMBL; AF129756; AAD18092.1; -; Genomic_DNA.
EMBL; BA000025; BAB63397.1; -; Genomic_DNA.
EMBL; AY070490; AAL49956.1; -; Genomic_DNA.
EMBL; AY216498; AAO21135.1; -; Genomic_DNA.
EMBL; BC034729; AAH34729.1; -; mRNA.
CCDS; CCDS4701.1; -.
PIR; A92755; QWHUX.
RefSeq; NP_000586.2; NM_000595.3.
RefSeq; NP_001153212.1; NM_001159740.2.
RefSeq; XP_011512917.1; XM_011514615.2.
RefSeq; XP_011512918.1; XM_011514616.2.
RefSeq; XP_011512919.1; XM_011514617.2.
RefSeq; XP_011512920.1; XM_011514618.1.
UniGene; Hs.36; -.
PDB; 1TNR; X-ray; 2.85 A; A=62-205.
PDB; 4MXV; X-ray; 3.20 A; A/B/D=62-205.
PDB; 4MXW; X-ray; 3.60 A; A/X=62-205.
PDBsum; 1TNR; -.
PDBsum; 4MXV; -.
PDBsum; 4MXW; -.
ProteinModelPortal; P01374; -.
SMR; P01374; -.
BioGrid; 110227; 8.
CORUM; P01374; -.
DIP; DIP-2910N; -.
IntAct; P01374; 7.
MINT; P01374; -.
STRING; 9606.ENSP00000403495; -.
BindingDB; P01374; -.
ChEMBL; CHEMBL2059; -.
DrugBank; DB00005; Etanercept.
GlyConnect; 354; -.
iPTMnet; P01374; -.
UniCarbKB; P01374; -.
BioMuta; LTA; -.
DMDM; 135940; -.
EPD; P01374; -.
PaxDb; P01374; -.
PeptideAtlas; P01374; -.
PRIDE; P01374; -.
DNASU; 4049; -.
Ensembl; ENST00000412851; ENSP00000412555; ENSG00000230279.
Ensembl; ENST00000418386; ENSP00000413450; ENSG00000226979.
Ensembl; ENST00000426845; ENSP00000402413; ENSG00000230279.
Ensembl; ENST00000436519; ENSP00000395976; ENSG00000231408.
Ensembl; ENST00000454550; ENSP00000416509; ENSG00000231408.
Ensembl; ENST00000454783; ENSP00000403495; ENSG00000226979.
GeneID; 4049; -.
KEGG; hsa:4049; -.
CTD; 4049; -.
DisGeNET; 4049; -.
EuPathDB; HostDB:ENSG00000226979.8; -.
GeneCards; LTA; -.
HGNC; HGNC:6709; LTA.
HPA; HPA007729; -.
MalaCards; LTA; -.
MIM; 153440; gene.
MIM; 607507; phenotype.
MIM; 610988; phenotype.
neXtProt; NX_P01374; -.
OpenTargets; ENSG00000226979; -.
Orphanet; 40050; Adult psoriatic arthritis.
PharmGKB; PA30474; -.
eggNOG; ENOG410IWT9; Eukaryota.
eggNOG; ENOG410YQC4; LUCA.
GeneTree; ENSGT00530000062992; -.
HOGENOM; HOG000048729; -.
HOVERGEN; HBG012516; -.
InParanoid; P01374; -.
KO; K05468; -.
OMA; QYPFHVP; -.
OrthoDB; EOG091G0HIG; -.
PhylomeDB; P01374; -.
TreeFam; TF332169; -.
Reactome; R-HSA-5668541; TNFR2 non-canonical NF-kB pathway.
Reactome; R-HSA-5669034; TNFs bind their physiological receptors.
Reactome; R-HSA-5676594; TNF receptor superfamily (TNFSF) members mediating non-canonical NF-kB pathway.
SIGNOR; P01374; -.
EvolutionaryTrace; P01374; -.
GeneWiki; Lymphotoxin_alpha; -.
GenomeRNAi; 4049; -.
PRO; PR:P01374; -.
Proteomes; UP000005640; Chromosome 6.
Bgee; ENSG00000226979; -.
CleanEx; HS_LTA; -.
ExpressionAtlas; P01374; baseline and differential.
Genevisible; P01374; HS.
GO; GO:0005615; C:extracellular space; IEA:UniProtKB-KW.
GO; GO:0005886; C:plasma membrane; TAS:Reactome.
GO; GO:0005125; F:cytokine activity; IEA:UniProtKB-KW.
GO; GO:0005102; F:signaling receptor binding; TAS:ProtInc.
GO; GO:0005164; F:tumor necrosis factor receptor binding; IEA:InterPro.
GO; GO:0006915; P:apoptotic process; TAS:ProtInc.
GO; GO:0007267; P:cell-cell signaling; TAS:ProtInc.
GO; GO:0050830; P:defense response to Gram-positive bacterium; IEA:Ensembl.
GO; GO:0006959; P:humoral immune response; IEA:Ensembl.
GO; GO:0048535; P:lymph node development; IEA:Ensembl.
GO; GO:0048147; P:negative regulation of fibroblast proliferation; IEA:Ensembl.
GO; GO:0044130; P:negative regulation of growth of symbiont in host; IEA:Ensembl.
GO; GO:0043065; P:positive regulation of apoptotic process; IEA:Ensembl.
GO; GO:0002876; P:positive regulation of chronic inflammatory response to antigenic stimulus; IEA:Ensembl.
GO; GO:0060252; P:positive regulation of glial cell proliferation; IEA:Ensembl.
GO; GO:0002925; P:positive regulation of humoral immune response mediated by circulating immunoglobulin; IEA:Ensembl.
GO; GO:0032729; P:positive regulation of interferon-gamma production; IEA:Ensembl.
GO; GO:0042493; P:response to drug; IEA:Ensembl.
GO; GO:0001666; P:response to hypoxia; IEA:Ensembl.
GO; GO:0032496; P:response to lipopolysaccharide; IEA:Ensembl.
GO; GO:0007584; P:response to nutrient; IEA:Ensembl.
GO; GO:0007165; P:signal transduction; TAS:ProtInc.
GO; GO:0033209; P:tumor necrosis factor-mediated signaling pathway; TAS:Reactome.
Gene3D; 2.60.120.40; -; 1.
InterPro; IPR006053; TNF.
InterPro; IPR002960; TNF_beta.
InterPro; IPR021184; TNF_CS.
InterPro; IPR006052; TNF_dom.
InterPro; IPR008983; Tumour_necrosis_fac-like_dom.
Pfam; PF00229; TNF; 1.
PRINTS; PR01234; TNECROSISFCT.
PRINTS; PR01236; TNFBETA.
SMART; SM00207; TNF; 1.
SUPFAM; SSF49842; SSF49842; 1.
PROSITE; PS00251; TNF_1; 1.
PROSITE; PS50049; TNF_2; 1.
1: Evidence at protein level;
3D-structure; Complete proteome; Cytokine; Direct protein sequencing;
Glycoprotein; Membrane; Polymorphism; Reference proteome; Secreted;
Signal.
SIGNAL 1 34
CHAIN 35 205 Lymphotoxin-alpha.
/FTId=PRO_0000034463.
CARBOHYD 41 41 O-linked (GalNAc...) threonine; partial.
{ECO:0000269|PubMed:1451807}.
CARBOHYD 96 96 N-linked (GlcNAc...) asparagine.
{ECO:0000269|PubMed:1451807}.
/FTId=CAR_000048.
VARIANT 13 13 C -> R (in dbSNP:rs2229094).
{ECO:0000269|PubMed:15489334,
ECO:0000269|Ref.10, ECO:0000269|Ref.11}.
/FTId=VAR_013023.
VARIANT 51 51 H -> P (in dbSNP:rs2229092).
{ECO:0000269|Ref.10, ECO:0000269|Ref.11}.
/FTId=VAR_013024.
VARIANT 60 60 T -> N (in allele TNFB*2;
dbSNP:rs1041981).
{ECO:0000269|PubMed:1451807,
ECO:0000269|PubMed:1670638,
ECO:0000269|Ref.10, ECO:0000269|Ref.11}.
/FTId=VAR_007511.
VARIANT 125 125 T -> P (in allele 8.1).
{ECO:0000269|PubMed:1671667}.
/FTId=VAR_007512.
STRAND 64 69 {ECO:0000244|PDB:1TNR}.
TURN 71 73 {ECO:0000244|PDB:4MXV}.
STRAND 74 76 {ECO:0000244|PDB:1TNR}.
STRAND 87 89 {ECO:0000244|PDB:1TNR}.
STRAND 93 95 {ECO:0000244|PDB:1TNR}.
STRAND 98 100 {ECO:0000244|PDB:1TNR}.
STRAND 103 117 {ECO:0000244|PDB:1TNR}.
HELIX 122 125 {ECO:0000244|PDB:1TNR}.
STRAND 129 138 {ECO:0000244|PDB:1TNR}.
STRAND 142 144 {ECO:0000244|PDB:1TNR}.
STRAND 146 155 {ECO:0000244|PDB:1TNR}.
STRAND 163 175 {ECO:0000244|PDB:1TNR}.
STRAND 180 186 {ECO:0000244|PDB:1TNR}.
HELIX 188 190 {ECO:0000244|PDB:1TNR}.
TURN 195 197 {ECO:0000244|PDB:1TNR}.
STRAND 198 204 {ECO:0000244|PDB:1TNR}.
SEQUENCE 205 AA; 22297 MW; 1BBD5E7D496A3A82 CRC64;
MTPPERLFLP RVCGTTLHLL LLGLLLVLLP GAQGLPGVGL TPSAAQTARQ HPKMHLAHST
LKPAAHLIGD PSKQNSLLWR ANTDRAFLQD GFSLSNNSLL VPTSGIYFVY SQVVFSGKAY
SPKATSSPLY LAHEVQLFSS QYPFHVPLLS SQKMVYPGLQ EPWLHSMYHG AAFQLTQGDQ
LSTHTDGIPH LVLSPSTVFF GAFAL


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