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Protein

CD40 ligand

Gene

CD40LG

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: -Experimental evidence at protein leveli

Functioni

Cytokine that binds to CD40/TNFRSF5 (PubMed:1280226). Costimulates T-cell proliferation and cytokine production. Its cross-linking on T-cells generates a costimulatory signal which enhances the production of IL4 and IL10 in conjunction with the TCR/CD3 ligation and CD28 costimulation (PubMed:8617933). Induces the activation of NF-kappa-B and kinases MAPK8 and PAK2 in T-cells. Induces tyrosine phosphorylation of isoform 3 of CD28 (PubMed:15067037). Mediates B-cell proliferation in the absence of co-stimulus as well as IgE production in the presence of IL4. Involved in immunoglobulin class switching (By similarity).By similarity3 Publications
Release of soluble CD40L from platelets is partially regulated by GP IIb/IIIa, actin polymerization, and an matrix metalloproteinases (MMP) inhibitor-sensitive pathway.1 Publication

GO - Molecular functioni

  • CD40 receptor binding Source: UniProtKB
  • cytokine activity Source: UniProtKB-KW
  • tumor necrosis factor receptor binding Source: InterPro

GO - Biological processi

  • activation of JUN kinase activity Source: UniProtKB
  • B cell differentiation Source: Ensembl
  • B cell proliferation Source: UniProtKB
  • immunoglobulin secretion Source: Ensembl
  • inflammatory response Source: UniProtKB
  • isotype switching Source: UniProtKB
  • leukocyte cell-cell adhesion Source: UniProtKB
  • negative regulation of apoptotic process Source: UniProtKB
  • platelet activation Source: UniProtKB
  • positive regulation of endothelial cell apoptotic process Source: BHF-UCL
  • positive regulation of interleukin-10 production Source: UniProtKB
  • positive regulation of interleukin-12 production Source: UniProtKB
  • positive regulation of interleukin-4 production Source: UniProtKB
  • positive regulation of NF-kappaB transcription factor activity Source: UniProtKB
  • positive regulation of T cell proliferation Source: UniProtKB
  • regulation of immune response Source: Reactome
  • regulation of immunoglobulin secretion Source: Ensembl
  • T cell costimulation Source: UniProtKB
  • tumor necrosis factor-mediated signaling pathway Source: Reactome

Keywordsi

Molecular functionCytokine

Enzyme and pathway databases

ReactomeiR-HSA-198933 Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell
R-HSA-5668541 TNFR2 non-canonical NF-kB pathway
R-HSA-5676594 TNF receptor superfamily (TNFSF) members mediating non-canonical NF-kB pathway
SIGNORiP29965

Names & Taxonomyi

Protein namesi
Recommended 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:
Gene namesi
Name:CD40LG
Synonyms:CD40L, TNFSF5, TRAP
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome X

Organism-specific databases

EuPathDBiHostDB:ENSG00000102245.7
HGNCiHGNC:11935 CD40LG
MIMi300386 gene
neXtProtiNX_P29965

Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

Topology

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Topological domaini1 – 22CytoplasmicSequence analysisAdd BLAST22
Transmembranei23 – 46Helical; Signal-anchor for type II membrane proteinSequence analysisAdd BLAST24
Topological domaini47 – 261ExtracellularSequence analysisAdd BLAST215

Keywords - Cellular componenti

Cell membrane, Membrane, Secreted

Pathology & Biotechi

Involvement in diseasei

Immunodeficiency with hyper-IgM, type 1 (HIGM1)11 Publications
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionImmunoglobulin 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.
See also OMIM:308230
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_00751336M → R in HIGM1. 2 PublicationsCorresponds to variant dbSNP:rs104894774Ensembl.1
Natural variantiVAR_01792538G → R in HIGM1. 1 Publication1
Natural variantiVAR_017929116G → R in HIGM1. 1
Natural variantiVAR_017930116G → S in HIGM1. 2 Publications1
Natural variantiVAR_007514123A → E in HIGM1. 1 PublicationCorresponds to variant dbSNP:rs104894778Ensembl.1
Natural variantiVAR_017926125H → R in HIGM1. 1 Publication1
Natural variantiVAR_007515126V → A in HIGM1. 1 Publication1
Natural variantiVAR_017931126V → D in HIGM1. 1
Natural variantiVAR_007516128 – 129SE → RG in HIGM1. 2
Natural variantiVAR_007517140W → C in HIGM1. 1 Publication1
Natural variantiVAR_007518140W → G in HIGM1. 1 PublicationCorresponds to variant dbSNP:rs104894777Ensembl.1
Natural variantiVAR_007519140W → R in HIGM1. 1 Publication1
Natural variantiVAR_017932143K → T in HIGM1. 1
Natural variantiVAR_007520144G → E in HIGM1. 1 PublicationCorresponds to variant dbSNP:rs886039326Ensembl.1
Natural variantiVAR_017922147T → N in HIGM1. 1 Publication1
Natural variantiVAR_007521155L → P in HIGM1. 2 PublicationsCorresponds to variant dbSNP:rs104894769Ensembl.1
Natural variantiVAR_017923170Y → C in HIGM1. 1 PublicationCorresponds to variant dbSNP:rs756468554Ensembl.1
Natural variantiVAR_017933173A → D in HIGM1. 1
Natural variantiVAR_017927174Q → R in HIGM1. 1 Publication1
Natural variantiVAR_017934176T → I in HIGM1. 1
Natural variantiVAR_017935195L → P in HIGM1. 1
Natural variantiVAR_017936208A → D in HIGM1. 1
Natural variantiVAR_007522211T → N in HIGM1. 1 Publication1
Natural variantiVAR_017937224H → Y in HIGM1. 1
Natural variantiVAR_017938226G → A in HIGM1. 1
Natural variantiVAR_007524227G → V in HIGM1. 3 PublicationsCorresponds to variant dbSNP:rs104894768Ensembl.1
Natural variantiVAR_007525227Missing in HIGM1. 1 Publication1
Natural variantiVAR_007526231L → S in HIGM1. 2 Publications1
Natural variantiVAR_007527235A → P in HIGM1. 2 PublicationsCorresponds to variant dbSNP:rs104894771Ensembl.1
Natural variantiVAR_017939237V → E in HIGM1. 1 Publication1
Natural variantiVAR_007528254T → M in HIGM1. 2 PublicationsCorresponds to variant dbSNP:rs193922136Ensembl.1
Natural variantiVAR_017940257G → D in HIGM1. 1
Natural variantiVAR_017928257G → S in HIGM1. 1 Publication1
Natural variantiVAR_017924258L → S in HIGM1. 1 Publication1

Keywords - Diseasei

Disease mutation

Organism-specific databases

DisGeNETi959
GeneReviewsiCD40LG
MalaCardsiCD40LG
MIMi308230 phenotype
OpenTargetsiENSG00000102245
Orphaneti101088 X-linked hyper-IgM syndrome
PharmGKBiPA36626

Chemistry databases

ChEMBLiCHEMBL3580491

Polymorphism and mutation databases

BioMutaiCD40LG
DMDMi231718

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00000344841 – 261CD40 ligand, membrane formAdd BLAST261
ChainiPRO_0000034485113 – 261CD40 ligand, soluble form1 PublicationAdd BLAST149

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Disulfide bondi178 ↔ 218Sequence analysis
Glycosylationi240N-linked (GlcNAc...) (complex) asparagine; alternate1 Publication1
Glycosylationi240N-linked (GlcNAc...) (high mannose) asparagine; alternate1 Publication1

Post-translational modificationi

The soluble form derives from the membrane form by proteolytic processing.1 Publication
N-linked glycan is a mixture of high mannose and complex type. Glycan structure does not influence binding affinity to CD40.1 Publication
Not O-glycosylated.

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sitei112 – 113Cleavage2

Keywords - PTMi

Disulfide bond, Glycoprotein

Proteomic databases

MaxQBiP29965
PaxDbiP29965
PeptideAtlasiP29965
PRIDEiP29965

PTM databases

GlyConnecti610
iPTMnetiP29965
PhosphoSitePlusiP29965
UniCarbKBiP29965

Miscellaneous databases

PMAP-CutDBiP29965

Expressioni

Tissue specificityi

Specifically expressed on activated CD4+ T-lymphocytes.

Gene expression databases

BgeeiENSG00000102245
CleanExiHS_CD40LG
ExpressionAtlasiP29965 baseline and differential
GenevisibleiP29965 HS

Organism-specific databases

HPAiHPA045827

Interactioni

Subunit structurei

Homotrimer (PubMed:8589998, PubMed:8626375, PubMed:11676606). Interacts with isoform 3 of CD28 (PubMed:15067037).4 Publications

GO - Molecular functioni

  • CD40 receptor binding Source: UniProtKB
  • cytokine activity Source: UniProtKB-KW
  • tumor necrosis factor receptor binding Source: InterPro

Protein-protein interaction databases

BioGridi107397, 9 interactors
DIPiDIP-3013N
STRINGi9606.ENSP00000359663

Structurei

Secondary structure

1261
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Beta strandi123 – 128Combined sources6
Beta strandi132 – 134Combined sources3
Beta strandi140 – 142Combined sources3
Beta strandi153 – 156Combined sources4
Turni157 – 159Combined sources3
Beta strandi160 – 165Combined sources6
Beta strandi167 – 179Combined sources13
Turni181 – 183Combined sources3
Beta strandi186 – 195Combined sources10
Beta strandi203 – 211Combined sources9
Beta strandi218 – 232Combined sources15
Beta strandi237 – 242Combined sources6
Helixi244 – 246Combined sources3
Beta strandi251 – 260Combined sources10

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB 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[»]
ProteinModelPortaliP29965
SMRiP29965
ModBaseiSearch...
MobiDBiSearch...

Miscellaneous databases

EvolutionaryTraceiP29965

Family & Domainsi

Sequence similaritiesi

Belongs to the tumor necrosis factor family.Curated

Keywords - Domaini

Signal-anchor, Transmembrane, Transmembrane helix

Phylogenomic databases

eggNOGiENOG410IVYF Eukaryota
ENOG4111TET LUCA
GeneTreeiENSGT00510000048489
HOGENOMiHOG000111291
HOVERGENiHBG079629
InParanoidiP29965
KOiK03161
OMAiSMKIFMY
OrthoDBiEOG091G0I9G
PhylomeDBiP29965
TreeFamiTF332169

Family and domain databases

Gene3Di2.60.120.40, 1 hit
InterProiView protein in InterPro
IPR003263 CD40L
IPR021184 TNF_CS
IPR006052 TNF_dom
IPR008983 Tumour_necrosis_fac-like_dom
PANTHERiPTHR11471:SF5 PTHR11471:SF5, 1 hit
PfamiView protein in Pfam
PF00229 TNF, 1 hit
PIRSFiPIRSF016527 TNF_5, 1 hit
PRINTSiPR01702 CD40LIGAND
SMARTiView protein in SMART
SM00207 TNF, 1 hit
SUPFAMiSSF49842 SSF49842, 1 hit
PROSITEiView protein in PROSITE
PS00251 TNF_1, 1 hit
PS50049 TNF_2, 1 hit

Sequencei

Sequence statusi: Complete.

Sequence processingi: The displayed sequence is further processed into a mature form.

P29965-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MIETYNQTSP RSAATGLPIS MKIFMYLLTV FLITQMIGSA LFAVYLHRRL
60 70 80 90 100
DKIEDERNLH EDFVFMKTIQ RCNTGERSLS LLNCEEIKSQ FEGFVKDIML
110 120 130 140 150
NKEETKKENS FEMQKGDQNP QIAAHVISEA SSKTTSVLQW AEKGYYTMSN
160 170 180 190 200
NLVTLENGKQ LTVKRQGLYY IYAQVTFCSN REASSQAPFI ASLCLKSPGR
210 220 230 240 250
FERILLRAAN THSSAKPCGQ QSIHLGGVFE LQPGASVFVN VTDPSQVSHG
260
TGFTSFGLLK L
Length:261
Mass (Da):29,274
Last modified:April 1, 1993 - v1
Checksum:i16F5CEB093BCC2BB
GO

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_00751336M → R in HIGM1. 2 PublicationsCorresponds to variant dbSNP:rs104894774Ensembl.1
Natural variantiVAR_01792538G → R in HIGM1. 1 Publication1
Natural variantiVAR_017929116G → R in HIGM1. 1
Natural variantiVAR_017930116G → S in HIGM1. 2 Publications1
Natural variantiVAR_007514123A → E in HIGM1. 1 PublicationCorresponds to variant dbSNP:rs104894778Ensembl.1
Natural variantiVAR_017926125H → R in HIGM1. 1 Publication1
Natural variantiVAR_007515126V → A in HIGM1. 1 Publication1
Natural variantiVAR_017931126V → D in HIGM1. 1
Natural variantiVAR_007516128 – 129SE → RG in HIGM1. 2
Natural variantiVAR_007517140W → C in HIGM1. 1 Publication1
Natural variantiVAR_007518140W → G in HIGM1. 1 PublicationCorresponds to variant dbSNP:rs104894777Ensembl.1
Natural variantiVAR_007519140W → R in HIGM1. 1 Publication1
Natural variantiVAR_017932143K → T in HIGM1. 1
Natural variantiVAR_007520144G → E in HIGM1. 1 PublicationCorresponds to variant dbSNP:rs886039326Ensembl.1
Natural variantiVAR_017922147T → N in HIGM1. 1 Publication1
Natural variantiVAR_007521155L → P in HIGM1. 2 PublicationsCorresponds to variant dbSNP:rs104894769Ensembl.1
Natural variantiVAR_017923170Y → C in HIGM1. 1 PublicationCorresponds to variant dbSNP:rs756468554Ensembl.1
Natural variantiVAR_017933173A → D in HIGM1. 1
Natural variantiVAR_017927174Q → R in HIGM1. 1 Publication1
Natural variantiVAR_017934176T → I in HIGM1. 1
Natural variantiVAR_017935195L → P in HIGM1. 1
Natural variantiVAR_017936208A → D in HIGM1. 1
Natural variantiVAR_007522211T → N in HIGM1. 1 Publication1
Natural variantiVAR_007523219G → R1 PublicationCorresponds to variant dbSNP:rs148594123Ensembl.1
Natural variantiVAR_017937224H → Y in HIGM1. 1
Natural variantiVAR_017938226G → A in HIGM1. 1
Natural variantiVAR_007524227G → V in HIGM1. 3 PublicationsCorresponds to variant dbSNP:rs104894768Ensembl.1
Natural variantiVAR_007525227Missing in HIGM1. 1 Publication1
Natural variantiVAR_007526231L → S in HIGM1. 2 Publications1
Natural variantiVAR_007527235A → P in HIGM1. 2 PublicationsCorresponds to variant dbSNP:rs104894771Ensembl.1
Natural variantiVAR_017939237V → E in HIGM1. 1 Publication1
Natural variantiVAR_007528254T → M in HIGM1. 2 PublicationsCorresponds to variant dbSNP:rs193922136Ensembl.1
Natural variantiVAR_017940257G → D in HIGM1. 1
Natural variantiVAR_017928257G → S in HIGM1. 1 Publication1
Natural variantiVAR_017924258L → S in HIGM1. 1 Publication1

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
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
CCDSiCCDS14659.1
PIRiS28017 I53476
RefSeqiNP_000065.1, NM_000074.2
UniGeneiHs.592244

Genome annotation databases

EnsembliENST00000370629; ENSP00000359663; ENSG00000102245
GeneIDi959
KEGGihsa:959
UCSCiuc004faa.4 human

Keywords - Coding sequence diversityi

Polymorphism

Similar proteinsi

Entry informationi

Entry nameiCD40L_HUMAN
AccessioniPrimary (citable) accession number: P29965
Entry historyiIntegrated into UniProtKB/Swiss-Prot: April 1, 1993
Last sequence update: April 1, 1993
Last modified: April 25, 2018
This is version 199 of the entry and version 1 of the sequence. See complete history.
Entry statusiReviewed (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.

Miscellaneousi

Keywords - Technical termi

3D-structure, Complete proteome, Direct protein sequencing, Reference proteome
UniProt is an ELIXIR core data resource
Main funding by: National Institutes of Health