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P29965 (CD40L_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Last modified April 16, 2014. Version 168. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (7) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Sequence annotation·Sequences·References·Web links·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
CD40 ligand

Short name=CD40-L
Alternative name(s):
T-cell antigen Gp39
TNF-related activation protein
Short name=TRAP
Tumor necrosis factor ligand superfamily member 5
CD_antigen=CD154

Cleaved into the following 2 chains:

  1. CD40 ligand, membrane form
  2. CD40 ligand, soluble form
Gene names
Name:CD40LG
Synonyms:CD40L, TNFSF5, TRAP
OrganismHomo sapiens (Human) [Reference proteome]
Taxonomic identifier9606 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo

Protein attributes

Sequence length261 AA.
Sequence statusComplete.
Sequence processingThe displayed sequence is further processed into a mature form.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

Mediates B-cell proliferation in the absence of co-stimulus as well as IgE production in the presence of IL-4. Involved in immunoglobulin class switching. Ref.10

Release of soluble CD40L from platelets is partially regulated by GP IIb/IIIa, actin polymerization, and an matrix metalloproteinases (MMP) inhibitor-sensitive pathway. Ref.10

Subunit structure

Homotrimer.

Subcellular location

Cell membrane; Single-pass type II membrane protein.

CD40 ligand, soluble form: Secreted.

Tissue specificity

Specifically expressed on activated CD4+ T-lymphocytes.

Post-translational modification

The soluble form derives from the membrane form by proteolytic processing.

N-linked glycan is a mixture of high mannose and complex type. Glycan structure does not influence binding affinity to CD40.

Not O-glycosylated. Ref.9

Involvement in disease

X-linked immunodeficiency with hyper-IgM 1 (HIGM1) [MIM:308230]: Immunoglobulin isotype switch defect characterized by elevated concentrations of serum IgM and decreased amounts of all other isotypes. Affected males present at an early age (usually within the first year of life) recurrent bacterial and opportunistic infections, including Pneumocystis carinii pneumonia and intractable diarrhea due to cryptosporidium infection. Despite substitution treatment with intravenous immunoglobulin, the overall prognosis is rather poor, with a death rate of about 10% before adolescence.
Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.3 Ref.13 Ref.14 Ref.15 Ref.16 Ref.17 Ref.18 Ref.19 Ref.20 Ref.21

Sequence similarities

Belongs to the tumor necrosis factor family.

Ontologies

Keywords
   Cellular componentCell membrane
Membrane
Secreted
   Coding sequence diversityPolymorphism
   DiseaseDisease mutation
   DomainSignal-anchor
Transmembrane
Transmembrane helix
   Molecular functionCytokine
   PTMDisulfide bond
Glycoprotein
   Technical term3D-structure
Complete proteome
Direct protein sequencing
Reference proteome
Gene Ontology (GO)
   Biological_processB cell differentiation

Inferred from electronic annotation. Source: Ensembl

B cell proliferation

Inferred from direct assay PubMed 8605945. Source: UniProtKB

immunoglobulin secretion

Inferred from electronic annotation. Source: Ensembl

inflammatory response

Inferred from direct assay PubMed 9468137. Source: UniProtKB

isotype switching

Inferred from sequence or structural similarity. Source: UniProtKB

leukocyte cell-cell adhesion

Non-traceable author statement PubMed 9468137. Source: UniProtKB

negative regulation of apoptotic process

Inferred from direct assay PubMed 12697681. Source: UniProtKB

platelet activation

Inferred from direct assay PubMed 9468137. Source: UniProtKB

positive regulation of endothelial cell apoptotic process

Inferred from direct assay PubMed 12885753. Source: BHF-UCL

positive regulation of interleukin-12 production

Inferred from direct assay PubMed 9922218. Source: UniProtKB

regulation of immune response

Traceable author statement. Source: Reactome

regulation of immunoglobulin secretion

Inferred from electronic annotation. Source: Ensembl

   Cellular_componentexternal side of plasma membrane

Inferred from electronic annotation. Source: Ensembl

extracellular space

Inferred from electronic annotation. Source: UniProtKB-KW

integral component of membrane

Non-traceable author statement PubMed 9468137. Source: UniProtKB

integral component of plasma membrane

Traceable author statement Ref.5. Source: ProtInc

plasma membrane

Traceable author statement. Source: Reactome

   Molecular_functionCD40 receptor binding

Inferred from physical interaction PubMed 9468137. Source: UniProtKB

Complete GO annotation...

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Chain1 – 261261CD40 ligand, membrane form
PRO_0000034484
Chain113 – 261149CD40 ligand, soluble form
PRO_0000034485

Regions

Topological domain1 – 2222Cytoplasmic Potential
Transmembrane23 – 4624Helical; Signal-anchor for type II membrane protein; Potential
Topological domain47 – 261215Extracellular Potential

Sites

Site112 – 1132Cleavage

Amino acid modifications

Glycosylation2401N-linked (GlcNAc...) (high mannose and complex)
CAR_000229
Disulfide bond178 ↔ 218 Potential

Natural variations

Natural variant361M → R in HIGM1. Ref.13 Ref.20
VAR_007513
Natural variant381G → R in HIGM1. Ref.18
VAR_017925
Natural variant1161G → R in HIGM1.
VAR_017929
Natural variant1161G → S in HIGM1. Ref.21
VAR_017930
Natural variant1231A → E in HIGM1. Ref.14
VAR_007514
Natural variant1251H → R in HIGM1. Ref.18
VAR_017926
Natural variant1261V → A in HIGM1. Ref.16
VAR_007515
Natural variant1261V → D in HIGM1.
VAR_017931
Natural variant128 – 1292SE → RG in HIGM1.
VAR_007516
Natural variant1401W → C in HIGM1. Ref.20
VAR_007517
Natural variant1401W → G in HIGM1. Ref.13
VAR_007518
Natural variant1401W → R in HIGM1. Ref.16
VAR_007519
Natural variant1431K → T in HIGM1.
VAR_017932
Natural variant1441G → E in HIGM1. Ref.16
VAR_007520
Natural variant1471T → N in HIGM1. Ref.21
VAR_017922
Natural variant1551L → P in HIGM1. Ref.15 Ref.19
VAR_007521
Natural variant1701Y → C in HIGM1. Ref.21
VAR_017923
Natural variant1731A → D in HIGM1.
VAR_017933
Natural variant1741Q → R in HIGM1. Ref.18
VAR_017927
Natural variant1761T → I in HIGM1.
VAR_017934
Natural variant1951L → P in HIGM1.
VAR_017935
Natural variant2081A → D in HIGM1.
VAR_017936
Natural variant2111T → N in HIGM1. Ref.15
VAR_007522
Natural variant2191G → R. Ref.19
Corresponds to variant rs148594123 [ dbSNP | Ensembl ].
VAR_007523
Natural variant2241H → Y in HIGM1.
VAR_017937
Natural variant2261G → A in HIGM1.
VAR_017938
Natural variant2271G → V in HIGM1. Ref.15 Ref.19 Ref.21
VAR_007524
Natural variant2271Missing in HIGM1. Ref.20
VAR_007525
Natural variant2311L → S in HIGM1. Ref.20 Ref.21
VAR_007526
Natural variant2351A → P in HIGM1. Ref.3 Ref.21
VAR_007527
Natural variant2371V → E in HIGM1. Ref.17
VAR_017939
Natural variant2541T → M in HIGM1. Ref.20 Ref.21
VAR_007528
Natural variant2571G → D in HIGM1.
VAR_017940
Natural variant2571G → S in HIGM1. Ref.18
VAR_017928
Natural variant2581L → S in HIGM1. Ref.21
VAR_017924

Secondary structure

........................... 261
Helix Strand Turn

Details...

Sequences

Sequence LengthMass (Da)Tools
P29965 [UniParc].

Last modified April 1, 1993. Version 1.
Checksum: 16F5CEB093BCC2BB

FASTA26129,274
        10         20         30         40         50         60 
MIETYNQTSP RSAATGLPIS MKIFMYLLTV FLITQMIGSA LFAVYLHRRL DKIEDERNLH 

        70         80         90        100        110        120 
EDFVFMKTIQ RCNTGERSLS LLNCEEIKSQ FEGFVKDIML NKEETKKENS FEMQKGDQNP 

       130        140        150        160        170        180 
QIAAHVISEA SSKTTSVLQW AEKGYYTMSN NLVTLENGKQ LTVKRQGLYY IYAQVTFCSN 

       190        200        210        220        230        240 
REASSQAPFI ASLCLKSPGR FERILLRAAN THSSAKPCGQ QSIHLGGVFE LQPGASVFVN 

       250        260 
VTDPSQVSHG TGFTSFGLLK L 

« Hide

References

« Hide 'large scale' references
[1]"Cloning of TRAP, a ligand for CD40 on human T cells."
Graf D., Korthaeuer U., Mages H.W., Senger G., Kroczek R.A.
Eur. J. Immunol. 22:3191-3194(1992) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[2]"The human T cell antigen gp39, a member of the TNF gene family, is a ligand for the CD40 receptor: expression of a soluble form of gp39 with B cell co-stimulatory activity."
Hollenbaugh D., Grosmaire L.S., Kullas C.D., Chalupny J.N., Braesch-Andersen S., Noelle R.J., Stamenkovic I., Ledbetter J.A., Aruffo A.
EMBO J. 11:4313-4321(1992) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[3]"The CD40 ligand, gp39, is defective in activated T cells from patients with X-linked hyper-IgM syndrome."
Aruffo A., Farrington M., Hollenbaugh D., Li X., Milatovich A., Nonoyama S., Bajorath J., Grosmaire L.S., Stenkamp R., Neubauer M., Roberts R.L., Noelle R.J., Ledbetter J.A., Francke U., Ochs H.D.
Cell 72:291-300(1993) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA], VARIANTS HIGM1 128-ARG-GLY-129 AND PRO-235.
[4]"Recombinant human CD40 ligand stimulates B cell proliferation and immunoglobulin E secretion."
Spriggs M.K., Armitage R.J., Strockbine L., Clifford K.N., Macduff B.M., Sato T.A., Maliszewski C.R., Fanslow W.C.
J. Exp. Med. 176:1543-1550(1992) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[5]"Human CD40-ligand: molecular cloning, cellular distribution and regulation of expression by factors controlling IgE production."
Gauchat J.-F., Aubry J.-P., Mazzei G.J., Life P., Jomotte T., Elson G., Bonnefoy J.-Y.
FEBS Lett. 315:259-266(1993) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[6]"Structural organization of the gene for CD40 ligand: molecular analysis for diagnosis of X-linked hyper-IgM syndrome."
Shimadzu M., Nunoi H., Terasaki H., Ninomiya R., Iwata M., Kanegasaka S., Matsuda I.
Biochim. Biophys. Acta 1260:67-72(1995) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[7]"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].
Tissue: Blood.
[8]"Human native soluble CD40L is a biologically active trimer, processed inside microsomes."
Pietravalle F., Lecoanet-Henchoz S., Blasey H., Aubry J.-P., Elson G., Edgerton M.D., Bonnefoy J.-Y., Gauchat J.-F.
J. Biol. Chem. 271:5965-5967(1996) [PubMed] [Europe PMC] [Abstract]
Cited for: PROTEIN SEQUENCE OF 113-117, PROTEOLYTIC PROCESSING.
[9]"Determination of carbohydrate structures N-linked to soluble CD154 and characterization of the interactions of CD40 with CD154 expressed in Pichia pastoris and Chinese hamster ovary cells."
Khandekar S.S., Silverman C., Wells-Marani J., Bacon A.M., Birrell H., Brigham-Burke M., DeMarini D.J., Jonak Z.L., Camilleri P., Fishman-Lobell J.
Protein Expr. Purif. 23:301-310(2001) [PubMed] [Europe PMC] [Abstract]
Cited for: STRUCTURE OF CARBOHYDRATE ON ASN-240, IDENTIFICATION BY MASS SPECTROMETRY.
[10]"Release of soluble CD40L from platelets is regulated by glycoprotein IIb/IIIa and actin polymerization."
Furman M.I., Krueger L.A., Linden M.D., Barnard M.R., Frelinger A.L. III, Michelson A.D.
J. Am. Coll. Cardiol. 43:2319-2325(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION.
[11]"2-A crystal structure of an extracellular fragment of human CD40 ligand."
Karpsusas M., Hsu Y.-M., Wang J.-H., Thompson J., Lederman S., Chess L., Thomas D.
Structure 3:1031-1039(1995) [PubMed] [Europe PMC] [Abstract]
Cited for: X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS) OF 116-261.
[12]"The role of polar interactions in the molecular recognition of CD40L with its receptor CD40."
Singh J., Garber E., van Vlijmen H., Karpsusas M., Hsu Y.-M., Zheng Z., Naismith J.H., Thomas D.
Protein Sci. 7:1124-1135(1998) [PubMed] [Europe PMC] [Abstract]
Cited for: 3D-STRUCTURE MODELING OF COMPLEX WITH CD40.
[13]"Defective expression of T-cell CD40 ligand causes X-linked immunodeficiency with hyper-IgM."
Korthaeuer U., Graf D., Mages H.W., Briere F., Padayachee M., Malcolm S., Ugazio A.G., Notarangelo L.D., Levinsky R.J., Kroczek R.A.
Nature 361:539-541(1993) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANTS HIGM1 ARG-36 AND GLY-140.
[14]"CD40 ligand mutations in X-linked immunodeficiency with hyper-IgM."
Disanto J.P., Bonnefoy J.-Y., Gauchat J.-F., Fischer A., de Saint Basile G.
Nature 361:541-543(1993) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANT HIGM1 GLU-123.
[15]"CD40 ligand gene defects responsible for X-linked hyper-IgM syndrome."
Allen R.C., Armitage R.J., Conley M.E., Rosenblatt H., Jenkins N.A., Copeland N.G., Bedell M.A., Edelhoff S., Disteche C.M., Simoneaux D.K., Fanslow W.C., Belmont J.W., Spriggs M.K.
Science 259:990-993(1993) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANTS HIGM1 PRO-155; ASN-211 AND VAL-227.
[16]"Characterization of nine novel mutations in the CD40 ligand gene in patients with X-linked hyper IgM syndrome of various ancestry."
Macchi P., Villa A., Strina D., Sacco M.G., Morali F., Brugnoni D., Giliani S., Mantuano E., Fasth A., Andersson B., Zegers B.J.M., Cavagni G., Reznick I., Levy J., Zan-Bar I., Porat Y., Airo P., Plebani A., Vezzoni P., Notarangelo L.D.
Am. J. Hum. Genet. 56:898-906(1995) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANTS HIGM1 ALA-126; ARG-140 AND GLU-144.
[17]"Signaling through CD40 rescues IgE but not IgG or IgA secretion in X-linked immunodeficiency with hyper-IgM."
Saiki O., Tanaka T., Wada Y., Uda H., Inoue A., Katada Y., Izeki M., Iwata M., Nunoi H., Matsuda I.
J. Clin. Invest. 95:510-514(1995) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANT HIGM1 GLU-237.
[18]"Mutation analysis in CD40 ligand deficiency leading to X-linked hypogammaglobulinemia with hyper IgM syndrome."
Katz F., Hinshelwood S., Rutland P., Jones A., Kinnon C., Morgan G.
Hum. Mutat. 8:223-228(1996) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANTS HIGM1 ARG-38; ARG-125; ARG-174 AND SER-257.
[19]"A single strand conformation polymorphism study of CD40 ligand. Efficient mutation analysis and carrier detection for X-linked hyper IgM syndrome."
Lin Q., Rohrer J., Allen R.C., Larche M., Greene J.M., Shigeoka A.O., Gatti R.A., Derauf D.C., Belmont J.W., Conley M.E.
J. Clin. Invest. 97:196-201(1996) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANTS HIGM1 PRO-155 AND VAL-227, VARIANT ARG-219.
[20]"Mutations of the CD40 ligand gene in 13 Japanese patients with X-linked hyper-IgM syndrome."
Nonoyama S., Shimadzu M., Toru H., Seyama K., Nunoi H., Neubauer M., Yata J., Och H.D.
Hum. Genet. 99:624-627(1997) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANTS HIGM1 ARG-36; CYS-140; GLY-227 DEL; SER-231 AND MET-254.
[21]"Mutations of the CD40 ligand gene and its effect on CD40 ligand expression in patients with X-linked hyper IgM syndrome."
Seyama K., Nonoyama S., Gangsaas I., Hollenbaugh D., Pabst H.F., Aruffo A., Ochs H.D.
Blood 92:2421-2434(1998) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANTS HIGM1 SER-116; ASN-147; CYS-170; VAL-227; SER-231; PRO-235; MET-254 AND SER-258.
+Additional computationally mapped references.

Web resources

CD40Lbase

CD40L defect database

GeneReviews

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
X68550 mRNA. Translation: CAA48554.1.
Z15017 mRNA. Translation: CAA78737.1.
X67878 mRNA. Translation: CAA48077.1.
L07414 mRNA. Translation: AAA35662.1.
D31797 Genomic DNA. Translation: BAA06599.1.
BC071754 mRNA. Translation: AAH71754.1.
BC074950 mRNA. Translation: AAH74950.1.
PIRI53476. S28017.
RefSeqNP_000065.1. NM_000074.2.
UniGeneHs.592244.

3D structure databases

PDBe
RCSB PDB
PDBj
EntryMethodResolution (Å)ChainPositionsPDBsum
1ALYX-ray2.00A116-261[»]
1I9RX-ray3.10A/B/C116-261[»]
3LKJX-ray2.50A/B/C121-261[»]
3QD6X-ray3.50A/B/C/D/E/F116-261[»]
ProteinModelPortalP29965.
SMRP29965. Positions 116-261.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid107397. 10 interactions.
DIPDIP-3013N.
STRING9606.ENSP00000359663.

Chemistry

DrugBankDB01076. Atorvastatin.

PTM databases

PhosphoSiteP29965.
UniCarbKBP29965.

Polymorphism databases

DMDM231718.

Proteomic databases

PaxDbP29965.
PRIDEP29965.

Protocols and materials databases

DNASU959.
StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENST00000370629; ENSP00000359663; ENSG00000102245.
GeneID959.
KEGGhsa:959.
UCSCuc004faa.3. human.

Organism-specific databases

CTD959.
GeneCardsGC0XP135730.
HGNCHGNC:11935. CD40LG.
HPAHPA045827.
MIM300386. gene.
308230. phenotype.
neXtProtNX_P29965.
Orphanet101088. X-linked hyper-IgM syndrome.
PharmGKBPA36626.
GenAtlasSearch...

Phylogenomic databases

eggNOGNOG39330.
HOGENOMHOG000111291.
HOVERGENHBG079629.
InParanoidP29965.
KOK03161.
OMAKIFMYLL.
OrthoDBEOG7ZPNKR.
PhylomeDBP29965.
TreeFamTF332169.

Enzyme and pathway databases

ReactomeREACT_6900. Immune System.

Gene expression databases

ArrayExpressP29965.
BgeeP29965.
CleanExHS_CD40LG.
GenevestigatorP29965.

Family and domain databases

Gene3D2.60.120.40. 1 hit.
InterProIPR021184. TNF_CS.
IPR006052. TNF_dom.
IPR003263. TNF_ligand_5.
IPR008983. Tumour_necrosis_fac-like_dom.
[Graphical view]
PfamPF00229. TNF. 1 hit.
[Graphical view]
PIRSFPIRSF016527. TNF_5. 1 hit.
PRINTSPR01702. CD40LIGAND.
SMARTSM00207. TNF. 1 hit.
[Graphical view]
SUPFAMSSF49842. SSF49842. 1 hit.
PROSITEPS00251. TNF_1. 1 hit.
PS50049. TNF_2. 1 hit.
[Graphical view]
ProtoNetSearch...

Other

EvolutionaryTraceP29965.
GeneWikiCD154.
GenomeRNAi959.
NextBio3996.
PMAP-CutDBP29965.
PROP29965.
SOURCESearch...

Entry information

Entry nameCD40L_HUMAN
AccessionPrimary (citable) accession number: P29965
Entry history
Integrated into UniProtKB/Swiss-Prot: April 1, 1993
Last sequence update: April 1, 1993
Last modified: April 16, 2014
This is version 168 of the entry and version 1 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny 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.

Relevant documents

SIMILARITY comments

Index of protein domains and families

PDB cross-references

Index of Protein Data Bank (PDB) cross-references

MIM cross-references

Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot

Human polymorphisms and disease mutations

Index of human polymorphisms and disease mutations

Human entries with polymorphisms or disease mutations

List of human entries with polymorphisms or disease mutations

Human chromosome X

Human chromosome X: entries, gene names and cross-references to MIM

Human cell differentiation molecules

CD nomenclature of surface proteins of human leucocytes and list of entries