Reviewed, UniProtKB/Swiss-Prot P01374 (TNFB_HUMAN)

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)

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › 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.
Involvement in disease	Genetic variations in LTA are associated with susceptibility to leprosy type 4 (LPRS4) [MIM:610988]; also known as susceptibility to age-dependent leprosy. Leprosy is a chronic infectious disease of peripheral sensory nerves caused by Mycobacterium leprae. Genetic variations in LTA are associated with susceptibility to psoriatic arthritis [MIM:607507]. Psoriasis is a chronic inflammatory dermatosis that affects approximately 2% of the population. It is characterized by red, scaly skin lesions that are usually found on the scalp, elbows, and knees, and may be associated with severe arthritis. Psoriatic arthritis has been defined as an inflammatory arthritis usually without any rheumatoid factor in serum (seronegative arthritis) associated with psoriasis.
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 Direct protein sequencing
Gene Ontology (GO)
Biological process	cell-cell signaling Ref.4 Traceable author statement. Source: ProtInc induction of apoptosis Ref.4 Traceable author statement. Source: ProtInc signal transduction Ref.4 Traceable author statement. Source: ProtInc
Cellular component	extracellular space Inferred from electronic annotation. Source: UniProtKB-KW membrane Inferred from electronic annotation. Source: InterPro
Molecular function	tumor necrosis factor receptor binding Inferred from electronic annotation. Source: InterPro
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
TNFRSF14	Q92956	1	EBI-524105,EBI-1056653

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

Glycosylation

96

1

N-linked (GlcNAc...)

CAR_000048

Natural variations

Natural variant

13

1

C → R: dbSNP rs2229094.

VAR_013023

Natural variant

51

1

H → P: dbSNP rs2229092.

VAR_013024

Natural variant

60

1

T → N in allele TNFB*2. dbSNP rs1041981.

VAR_007511

Natural variant

125

1

T → P in allele 8.1.

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)
	P01374-1 [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: 3555974] [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: 3001109] [Abstract] Cited for: NUCLEOTIDE SEQUENCE.
[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: 3536896] [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: 6334807] [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: 1353024] [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: 8499947] [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: 10202016] [Abstract] Cited for: NUCLEOTIDE SEQUENCE.
[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: 14656967] [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 program for genomic applications 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, environmental genome project, NIEHS ES15478, Department of Genome Sciences, Seattle, WA (URL: http://egp.gs.washington.edu)." Rieder M.J., Livingston R.J., Daniels M.R., Montoya M.A., Chung M.-W., Miyamoto K.E., Nguyen C.P., Nguyen D.A., Poel C.L., Robertson P.D., Schackwitz W.S., Sherwood J.K., Witrak L.A., Nickerson D.A. 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: 15489334] [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: 1451807] [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: 1733919] [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: 8387891] [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: 1670638] [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: 1671667] [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: 12746914] [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: 17353895] [Abstract] Cited for: INVOLVEMENT IN LPRS4.
+	Additional computationally mapped references.

Web resources

Wikipedia

Lymphotoxin entry

Atlas of Genetics and Cytogenetics in Oncology and Haematology

SeattleSNPs

SHMPD

The Singapore human mutation and polymorphism database

Cross-references

Sequence databases

EMBLGenBankDDBJ

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.
A06316 Unassigned RNA. Translation: CAA00536.1.

PIR

QWHUX. A92755.

RefSeq

NP_000586.2.

UniGene

Hs.36

3D structure databases

PDBMSD

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

ModBase

Search...

Protein-protein interaction databases

DIP

DIP:2910N.

IntAct

P01374.

PTM databases

GlycoSuiteDB

P01374.

Polymorphism databases

NIEHS-SNPs

Search...

Genome annotation databases

Ensembl

ENSG00000204496. Homo sapiens. [Contig view]

GeneID

4049.

KEGG

hsa:4049.

Organism-specific databases

H-InvDB

HIX0025078.
HIX0057996.
HIX0058147.

HGNC

HGNC:6709. LTA.

HPA

HPA007729.

MIM

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

PharmGKB

PA26616.

GenAtlas

Search...

GeneCards

Search...

Phylogenomic databases

HOGENOM

P01374.

HOVERGEN

P01374.

Gene expression databases

ArrayExpress

P01374.

CleanEx

HS_LTA.

GermOnline

ENSG00000204496. Homo sapiens.

Family and domain databases

InterPro

IPR006053. TNF_abc.
IPR002960. TNF_beta.
IPR006052. TNF_family.
IPR008983. Tumour_necrosis_fac-like.
[Graphical view]

Gene3D

G3DSA:2.60.120.40. Tumour_necrosis_fac-like. 1 hit.

Pfam

PF00229. TNF. 1 hit.
[Graphical view]

PRINTS

PR01234. TNECROSISFCT.
PR01236. TNFBETA.

ProDom

PD002012. TNF_subf. 1 hit.
[Graphical view] [Entries sharing at least one domain]

SMART

SM00207. TNF. 1 hit.
[Graphical view]

PROSITE

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

ProtoNet

Search...

Other Resources

DrugBank

DB00005. Etanercept.

LinkHub

P01374.

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:	November 25, 2008
This is version 110 of the entry and version 2 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation project

HPI (Human Proteome Initiative)