ID TNFB_HUMAN Reviewed; 205 AA. AC P01374; Q8N4C3; Q9UKS8; DT 21-JUL-1986, integrated into UniProtKB/Swiss-Prot. DT 01-JUL-1989, sequence version 2. DT 13-FEB-2019, entry version 200. DE RecName: Full=Lymphotoxin-alpha; DE Short=LT-alpha; DE AltName: Full=TNF-beta; DE AltName: Full=Tumor necrosis factor ligand superfamily member 1; DE Flags: Precursor; GN Name=LTA; Synonyms=TNFB, TNFSF1; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; OC Catarrhini; Hominidae; Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA]. RX PubMed=3555974; RA Nedospasov S.A., Shakhov A.N., Turetskaya R.L., Mett V.A., RA Azizov M.M., Georgiev G.P., Korobko V.G., Dobrynin V.N., RA Filippov S.A., Bystrov N.S., Boldyreva E.F., Chuvpilo S.A., RA Chumakov A.M., Shingarova L.N., Ovchinnikov Y.A.; RT "Tandem arrangement of genes coding for tumor necrosis factor (TNF- RT alpha) and lymphotoxin (TNF-beta) in the human genome."; RL Cold Spring Harb. Symp. Quant. Biol. 51:611-624(1986). RN [2] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA]. RX PubMed=3001109; DOI=10.1002/jcb.240290302; RA Nedwin G.E., Jarrett-Nedwin J., Smith D.H., Naylor S.L., RA Sakaguchi A.Y., Goeddel D.V., Gray P.W.; RT "Structure and chromosomal localization of the human lymphotoxin RT gene."; RL J. Cell. Biochem. 29:171-181(1985). RN [3] RP NUCLEOTIDE SEQUENCE [MRNA]. RX PubMed=3536896; RA Kobayashi Y., Miyamoto D., Asada M., Obinata M., Osawa T.; RT "Cloning and expression of human lymphotoxin mRNA derived from a human RT T cell hybridoma."; RL J. Biochem. 100:727-733(1986). RN [4] RP NUCLEOTIDE SEQUENCE [MRNA]. RX PubMed=6334807; DOI=10.1038/312721a0; RA Gray P.W., Aggarwal B.B., Benton C.V., Bringman T.S., Henzel W.J., RA Jarrett J.A., Leung D.W., Moffat B., Ng P., Svedersky L.P., RA Palladino M.A., Nedwin G.E.; RT "Cloning and expression of cDNA for human lymphotoxin, a lymphokine RT with tumour necrosis activity."; RL Nature 312:721-724(1984). RN [5] RP NUCLEOTIDE SEQUENCE [MRNA]. RX PubMed=1353024; DOI=10.1016/0014-5793(92)80425-G; RA Matsuyama N., Okawa N., Tsukii Y., Endo T., Kaji A.; RT "Nucleotide sequence of a cDNA encoding human tumor necrosis factor RT beta from B lymphoblastoid cell RPMI 1788."; RL FEBS Lett. 302:141-144(1992). RN [6] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA]. RX PubMed=8499947; DOI=10.1038/ng0293-137; RA Iris F.J.M., Bougueleret L., Prieur S., Caterina D., Primas G., RA Perrot V., Jurka J., Rodriguez-Tome P., Claverie J.-M., Dausset J., RA Cohen D.; RT "Dense Alu clustering and a potential new member of the NF kappa B RT family within a 90 kilobase HLA class III segment."; RL Nat. Genet. 3:137-145(1993). RN [7] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA]. RX PubMed=10202016; RA Neville M.J., Campbell R.D.; RT "A new member of the Ig superfamily and a V-ATPase G subunit are among RT the predicted products of novel genes close to the TNF locus in the RT human MHC."; RL J. Immunol. 162:4745-4754(1999). RN [8] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=14656967; DOI=10.1101/gr.1736803; RA Xie T., Rowen L., Aguado B., Ahearn M.E., Madan A., Qin S., RA Campbell R.D., Hood L.; RT "Analysis of the gene-dense major histocompatibility complex class III RT region and its comparison to mouse."; RL Genome Res. 13:2621-2636(2003). RN [9] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RA Shiina S., Tamiya G., Oka A., Inoko H.; RT "Homo sapiens 2,229,817bp genomic DNA of 6p21.3 HLA class I region."; RL Submitted (SEP-1999) to the EMBL/GenBank/DDBJ databases. RN [10] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANTS ARG-13; PRO-51 AND RP ASN-60. RG SeattleSNPs variation discovery resource; RL Submitted (DEC-2001) to the EMBL/GenBank/DDBJ databases. RN [11] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANTS ARG-13; PRO-51 AND RP ASN-60. RG NIEHS SNPs program; RL Submitted (JAN-2003) to the EMBL/GenBank/DDBJ databases. RN [12] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], AND VARIANT ARG-13. RC TISSUE=Lymph; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA RT project: the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [13] RP PARTIAL PROTEIN SEQUENCE, GLYCOSYLATION AT THR-41 AND ASN-96, AND RP VARIANT ASN-60. RX PubMed=1451807; DOI=10.1016/0014-5793(92)81467-Z; RA Voigt C.G., Maurer-Fogy I., Adolf G.R.; RT "Natural human tumor necrosis factor beta (lymphotoxin). Variable O- RT glycosylation at Thr7, proteolytic processing, and allelic RT variation."; RL FEBS Lett. 314:85-88(1992). RN [14] RP FUNCTION, SUBUNIT, AND INTERACTION WITH TNFRSF14. RX PubMed=9462508; DOI=10.1016/S1074-7613(00)80455-0; RA Mauri D.N., Ebner R., Montgomery R.I., Kochel K.D., Cheung T.C., RA Yu G.-L., Ruben S., Murphy M., Eisenberg R.J., Cohen G.H., Spear P.G., RA Ware C.F.; RT "LIGHT, a new member of the TNF superfamily, and lymphotoxin alpha are RT ligands for herpesvirus entry mediator."; RL Immunity 8:21-30(1998). RN [15] RP X-RAY CRYSTALLOGRAPHY (1.9 ANGSTROMS). RX PubMed=1733919; RA Eck M.J., Ultsch M., Rinderknecht E., de Vos A.M., Sprang S.R.; RT "The structure of human lymphotoxin (tumor necrosis factor-beta) at RT 1.9-A resolution."; RL J. Biol. Chem. 267:2119-2122(1992). RN [16] RP X-RAY CRYSTALLOGRAPHY (2.85 ANGSTROMS) OF 61-205 OF COMPLEX WITH RP TNFR1. RX PubMed=8387891; DOI=10.1016/0092-8674(93)90132-A; RA Banner D.W., D'Arcy A., Janes W., Gentz R., Schoenfeld H.-J., RA Broger C., Loetscher H., Lesslauer W.; RT "Crystal structure of the soluble human 55 kd TNF receptor-human TNF RT beta complex: implications for TNF receptor activation."; RL Cell 73:431-445(1993). RN [17] RP VARIANT ASN-60. RX PubMed=1670638; DOI=10.1084/jem.173.1.209; RA Messer G., Spengler U., Jung M.C., Honold G., Bloemer K., Pape G.R., RA Riethmueller G., Weiss E.H.; RT "Polymorphic structure of the tumor necrosis factor (TNF) locus: an RT NcoI polymorphism in the first intron of the human TNF-beta gene RT correlates with a variant amino acid in position 26 and a reduced RT level of TNF-beta production."; RL J. Exp. Med. 173:209-219(1991). RN [18] RP VARIANT PRO-125. RX PubMed=1671667; DOI=10.1007/BF00211695; RA Abraham L.J., Du D.C., Zahedi K., Dawkins R.L., Whitehead A.S.; RT "Haplotypic polymorphisms of the TNFB gene."; RL Immunogenetics 33:50-53(1991). RN [19] RP INVOLVEMENT IN PSORIATIC ARTHRITIS SUSCEPTIBILITY. RX PubMed=12746914; DOI=10.1002/art.10935; RA Balding J., Kane D., Livingstone W., Mynett-Johnson L., Bresnihan B., RA Smith O., FitzGerald O.; RT "Cytokine gene polymorphisms: association with psoriatic arthritis RT susceptibility and severity."; RL Arthritis Rheum. 48:1408-1413(2003). RN [20] RP INVOLVEMENT IN LPRS4. RX PubMed=17353895; DOI=10.1038/ng2000; RA Alcaies A., Alter A., Antoni G., Orlova M., Nguyen V.T., Singh M., RA Vanderborght P.R., Katoch K., Mira M.T., Vu H.T., Ngyuen T.H., RA Nguyen N.B., Moraes M., Mehra N., Schurr E., Abel L.; RT "Stepwise replication identifies a low-producing lymphotoxin-alpha RT allele as a major risk factor for early-onset leprosy."; RL Nat. Genet. 39:517-522(2007). CC -!- FUNCTION: Cytokine that in its homotrimeric form binds to CC TNFRSF1A/TNFR1, TNFRSF1B/TNFBR and TNFRSF14/HVEM (PubMed:9462508). CC In its heterotrimeric form with LTB binds to TNFRSF3/LTBR. CC Lymphotoxin is produced by lymphocytes and is cytotoxic for a wide CC range of tumor cells in vitro and in vivo. CC {ECO:0000269|PubMed:9462508}. CC -!- SUBUNIT: Homotrimer, and heterotrimer of either two LTB and one CC LTA subunits or (less prevalent) two LTA and one LTB subunits. CC Interacts with TNFRSF14 (PubMed:9462508). CC {ECO:0000269|PubMed:9462508}. CC -!- SUBCELLULAR LOCATION: Secreted. Membrane. Note=The homotrimer is CC secreted. The heterotrimer is membrane-associated. CC -!- POLYMORPHISM: A polymorphism in LTA accounts, in part, for CC susceptibility to leprosy linked to chromosome 6p21.3 (LPRS4) CC [MIM:610988]. CC -!- DISEASE: Psoriatic arthritis (PSORAS) [MIM:607507]: An CC inflammatory, seronegative arthritis associated with psoriasis. It CC is a heterogeneous disorder ranging from a mild, non-destructive CC disease to a severe, progressive, erosive arthropathy. Five types CC of psoriatic arthritis have been defined: asymmetrical CC oligoarthritis characterized by primary involvement of the small CC joints of the fingers or toes; asymmetrical arthritis which CC involves the joints of the extremities; symmetrical polyarthritis CC characterized by a rheumatoid like pattern that can involve hands, CC wrists, ankles, and feet; arthritis mutilans, which is a rare but CC deforming and destructive condition; arthritis of the sacroiliac CC joints and spine (psoriatic spondylitis). CC {ECO:0000269|PubMed:12746914}. Note=Disease susceptibility is CC associated with variations affecting the gene represented in this CC entry. CC -!- SIMILARITY: Belongs to the tumor necrosis factor family. CC {ECO:0000305}. CC -!- WEB RESOURCE: Name=Wikipedia; Note=Lymphotoxin entry; CC URL="https://en.wikipedia.org/wiki/Lymphotoxin"; CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology CC and Haematology; CC URL="http://atlasgeneticsoncology.org/Genes/LTAID41209ch6p21.html"; CC -!- WEB RESOURCE: Name=NIEHS-SNPs; CC URL="http://egp.gs.washington.edu/data/lta/"; CC -!- WEB RESOURCE: Name=SeattleSNPs; CC URL="http://pga.gs.washington.edu/data/lta/"; CC -!- WEB RESOURCE: Name=SHMPD; Note=The Singapore human mutation and CC polymorphism database; CC URL="http://shmpd.bii.a-star.edu.sg/gene.php?genestart=A&genename=LTA"; CC ----------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC ----------------------------------------------------------------------- DR EMBL; X01393; CAA25649.1; -; mRNA. DR EMBL; X02911; CAA26670.1; -; Genomic_DNA. DR EMBL; D00102; BAA00064.1; -; mRNA. DR EMBL; M16441; AAA61199.1; -; Genomic_DNA. DR EMBL; D12614; BAA02139.1; -; mRNA. DR EMBL; M55913; AAB59455.1; -; Genomic_DNA. DR EMBL; Z15026; CAA78746.1; -; Genomic_DNA. DR EMBL; Y14768; CAA75071.1; -; Genomic_DNA. DR EMBL; AF129756; AAD18092.1; -; Genomic_DNA. DR EMBL; BA000025; BAB63397.1; -; Genomic_DNA. DR EMBL; AY070490; AAL49956.1; -; Genomic_DNA. DR EMBL; AY216498; AAO21135.1; -; Genomic_DNA. DR EMBL; BC034729; AAH34729.1; -; mRNA. DR CCDS; CCDS4701.1; -. DR PIR; A92755; QWHUX. DR RefSeq; NP_000586.2; NM_000595.3. DR RefSeq; NP_001153212.1; NM_001159740.2. DR RefSeq; XP_011512917.1; XM_011514615.2. DR RefSeq; XP_011512918.1; XM_011514616.2. DR RefSeq; XP_011512919.1; XM_011514617.2. DR RefSeq; XP_011512920.1; XM_011514618.1. DR UniGene; Hs.36; -. DR PDB; 1TNR; X-ray; 2.85 A; A=62-205. DR PDB; 4MXV; X-ray; 3.20 A; A/B/D=62-205. DR PDB; 4MXW; X-ray; 3.60 A; A/X=62-205. DR PDBsum; 1TNR; -. DR PDBsum; 4MXV; -. DR PDBsum; 4MXW; -. DR ProteinModelPortal; P01374; -. DR SMR; P01374; -. DR BioGrid; 110227; 10. DR CORUM; P01374; -. DR DIP; DIP-2910N; -. DR IntAct; P01374; 8. DR MINT; P01374; -. DR STRING; 9606.ENSP00000403495; -. DR BindingDB; P01374; -. DR ChEMBL; CHEMBL2059; -. DR DrugBank; DB00005; Etanercept. DR GlyConnect; 354; -. DR iPTMnet; P01374; -. DR UniCarbKB; P01374; -. DR BioMuta; LTA; -. DR DMDM; 135940; -. DR EPD; P01374; -. DR PaxDb; P01374; -. DR PeptideAtlas; P01374; -. DR PRIDE; P01374; -. DR ProteomicsDB; 51378; -. DR DNASU; 4049; -. DR Ensembl; ENST00000412851; ENSP00000412555; ENSG00000230279. DR Ensembl; ENST00000418386; ENSP00000413450; ENSG00000226979. DR Ensembl; ENST00000426845; ENSP00000402413; ENSG00000230279. DR Ensembl; ENST00000436519; ENSP00000395976; ENSG00000231408. DR Ensembl; ENST00000454550; ENSP00000416509; ENSG00000231408. DR Ensembl; ENST00000454783; ENSP00000403495; ENSG00000226979. DR GeneID; 4049; -. DR KEGG; hsa:4049; -. DR CTD; 4049; -. DR DisGeNET; 4049; -. DR EuPathDB; HostDB:ENSG00000226979.8; -. DR GeneCards; LTA; -. DR HGNC; HGNC:6709; LTA. DR HPA; HPA007729; -. DR MalaCards; LTA; -. DR MIM; 153440; gene. DR MIM; 607507; phenotype. DR MIM; 610988; phenotype. DR neXtProt; NX_P01374; -. DR OpenTargets; ENSG00000226979; -. DR PharmGKB; PA30474; -. DR eggNOG; ENOG410IWT9; Eukaryota. DR eggNOG; ENOG410YQC4; LUCA. DR GeneTree; ENSGT00940000153265; -. DR HOGENOM; HOG000048729; -. DR HOVERGEN; HBG012516; -. DR InParanoid; P01374; -. DR KO; K05468; -. DR OMA; FPKATPT; -. DR OrthoDB; 1124938at2759; -. DR PhylomeDB; P01374; -. DR TreeFam; TF332169; -. DR Reactome; R-HSA-5668541; TNFR2 non-canonical NF-kB pathway. DR Reactome; R-HSA-5669034; TNFs bind their physiological receptors. DR Reactome; R-HSA-5676594; TNF receptor superfamily (TNFSF) members mediating non-canonical NF-kB pathway. DR SIGNOR; P01374; -. DR EvolutionaryTrace; P01374; -. DR GeneWiki; Lymphotoxin_alpha; -. DR GenomeRNAi; 4049; -. DR PRO; PR:P01374; -. DR Proteomes; UP000005640; Chromosome 6. DR Bgee; ENSG00000226979; Expressed in 86 organ(s), highest expression level in dorsal plus ventral thalamus. DR Genevisible; P01374; HS. DR GO; GO:0005615; C:extracellular space; IEA:UniProtKB-KW. DR GO; GO:0005886; C:plasma membrane; TAS:Reactome. DR GO; GO:0005125; F:cytokine activity; IEA:UniProtKB-KW. DR GO; GO:0005102; F:signaling receptor binding; TAS:ProtInc. DR GO; GO:0005164; F:tumor necrosis factor receptor binding; IEA:InterPro. DR GO; GO:0006915; P:apoptotic process; TAS:ProtInc. DR GO; GO:0007267; P:cell-cell signaling; TAS:ProtInc. DR GO; GO:0050830; P:defense response to Gram-positive bacterium; IEA:Ensembl. DR GO; GO:0006959; P:humoral immune response; IEA:Ensembl. DR GO; GO:0048535; P:lymph node development; IEA:Ensembl. DR GO; GO:0048147; P:negative regulation of fibroblast proliferation; IEA:Ensembl. DR GO; GO:0044130; P:negative regulation of growth of symbiont in host; IEA:Ensembl. DR GO; GO:0043065; P:positive regulation of apoptotic process; IEA:Ensembl. DR GO; GO:0002876; P:positive regulation of chronic inflammatory response to antigenic stimulus; IEA:Ensembl. DR GO; GO:0060252; P:positive regulation of glial cell proliferation; IEA:Ensembl. DR GO; GO:0002925; P:positive regulation of humoral immune response mediated by circulating immunoglobulin; IEA:Ensembl. DR GO; GO:0032729; P:positive regulation of interferon-gamma production; IEA:Ensembl. DR GO; GO:0042493; P:response to drug; IEA:Ensembl. DR GO; GO:0001666; P:response to hypoxia; IEA:Ensembl. DR GO; GO:0032496; P:response to lipopolysaccharide; IEA:Ensembl. DR GO; GO:0007584; P:response to nutrient; IEA:Ensembl. DR GO; GO:0007165; P:signal transduction; TAS:ProtInc. DR GO; GO:0033209; P:tumor necrosis factor-mediated signaling pathway; TAS:Reactome. DR CDD; cd00184; TNF; 1. DR Gene3D; 2.60.120.40; -; 1. DR InterPro; IPR006053; TNF. DR InterPro; IPR002960; TNF_beta. DR InterPro; IPR021184; TNF_CS. DR InterPro; IPR006052; TNF_dom. DR InterPro; IPR008983; Tumour_necrosis_fac-like_dom. DR Pfam; PF00229; TNF; 1. DR PRINTS; PR01234; TNECROSISFCT. DR PRINTS; PR01236; TNFBETA. DR SMART; SM00207; TNF; 1. DR SUPFAM; SSF49842; SSF49842; 1. DR PROSITE; PS00251; TNF_1; 1. DR PROSITE; PS50049; TNF_2; 1. PE 1: Evidence at protein level; KW 3D-structure; Complete proteome; Cytokine; Direct protein sequencing; KW Glycoprotein; Membrane; Polymorphism; Reference proteome; Secreted; KW Signal. FT SIGNAL 1 34 FT CHAIN 35 205 Lymphotoxin-alpha. FT /FTId=PRO_0000034463. FT CARBOHYD 41 41 O-linked (GalNAc...) threonine; partial. FT {ECO:0000269|PubMed:1451807}. FT CARBOHYD 96 96 N-linked (GlcNAc...) asparagine. FT {ECO:0000269|PubMed:1451807}. FT /FTId=CAR_000048. FT VARIANT 13 13 C -> R (in dbSNP:rs2229094). FT {ECO:0000269|PubMed:15489334, FT ECO:0000269|Ref.10, ECO:0000269|Ref.11}. FT /FTId=VAR_013023. FT VARIANT 51 51 H -> P (in dbSNP:rs2229092). FT {ECO:0000269|Ref.10, ECO:0000269|Ref.11}. FT /FTId=VAR_013024. FT VARIANT 60 60 T -> N (in allele TNFB*2; FT dbSNP:rs1041981). FT {ECO:0000269|PubMed:1451807, FT ECO:0000269|PubMed:1670638, FT ECO:0000269|Ref.10, ECO:0000269|Ref.11}. FT /FTId=VAR_007511. FT VARIANT 125 125 T -> P (in allele 8.1). FT {ECO:0000269|PubMed:1671667}. FT /FTId=VAR_007512. FT STRAND 64 69 {ECO:0000244|PDB:1TNR}. FT TURN 71 73 {ECO:0000244|PDB:4MXV}. FT STRAND 74 76 {ECO:0000244|PDB:1TNR}. FT STRAND 87 89 {ECO:0000244|PDB:1TNR}. FT STRAND 93 95 {ECO:0000244|PDB:1TNR}. FT STRAND 98 100 {ECO:0000244|PDB:1TNR}. FT STRAND 103 117 {ECO:0000244|PDB:1TNR}. FT HELIX 122 125 {ECO:0000244|PDB:1TNR}. FT STRAND 129 138 {ECO:0000244|PDB:1TNR}. FT STRAND 142 144 {ECO:0000244|PDB:1TNR}. FT STRAND 146 155 {ECO:0000244|PDB:1TNR}. FT STRAND 163 175 {ECO:0000244|PDB:1TNR}. FT STRAND 180 186 {ECO:0000244|PDB:1TNR}. FT HELIX 188 190 {ECO:0000244|PDB:1TNR}. FT TURN 195 197 {ECO:0000244|PDB:1TNR}. FT STRAND 198 204 {ECO:0000244|PDB:1TNR}. SQ 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 //