CD40L_HUMAN
ID CD40L_HUMAN Reviewed; 261 AA.
AC P29965;
DT 01-APR-1993, integrated into UniProtKB/Swiss-Prot.
DT 01-APR-1993, sequence version 1.
DT 03-AUG-2022, entry version 226.
DE RecName: Full=CD40 ligand;
DE Short=CD40-L;
DE AltName: Full=T-cell antigen Gp39;
DE AltName: Full=TNF-related activation protein;
DE Short=TRAP;
DE AltName: Full=Tumor necrosis factor ligand superfamily member 5;
DE AltName: CD_antigen=CD154;
DE Contains:
DE RecName: Full=CD40 ligand, membrane form;
DE Contains:
DE RecName: Full=CD40 ligand, soluble form {ECO:0000303|PubMed:8626375};
DE Short=sCD40L {ECO:0000303|PubMed:31331973};
GN Name=CD40LG; Synonyms=CD40L, TNFSF5, TRAP;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], AND FUNCTION.
RX PubMed=1280226; DOI=10.1002/eji.1830221226;
RA Graf D., Korthaeuer U., Mages H.W., Senger G., Kroczek R.A.;
RT "Cloning of TRAP, a ligand for CD40 on human T cells.";
RL Eur. J. Immunol. 22:3191-3194(1992).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=1385114; DOI=10.1002/j.1460-2075.1992.tb05530.x;
RA Hollenbaugh D., Grosmaire L.S., Kullas C.D., Chalupny J.N.,
RA Braesch-Andersen S., Noelle R.J., Stamenkovic I., Ledbetter J.A.,
RA Aruffo A.;
RT "The human T cell antigen gp39, a member of the TNF gene family, is a
RT ligand for the CD40 receptor: expression of a soluble form of gp39 with B
RT cell co-stimulatory activity.";
RL EMBO J. 11:4313-4321(1992).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA], AND VARIANTS HIGM1 128-ARG-GLY-129 AND PRO-235.
RX PubMed=7678782; DOI=10.1016/0092-8674(93)90668-g;
RA Aruffo A., Farrington M., Hollenbaugh D., Li X., Milatovich A.,
RA Nonoyama S., Bajorath J., Grosmaire L.S., Stenkamp R., Neubauer M.,
RA Roberts R.L., Noelle R.J., Ledbetter J.A., Francke U., Ochs H.D.;
RT "The CD40 ligand, gp39, is defective in activated T cells from patients
RT with X-linked hyper-IgM syndrome.";
RL Cell 72:291-300(1993).
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=1281209; DOI=10.1084/jem.176.6.1543;
RA Spriggs M.K., Armitage R.J., Strockbine L., Clifford K.N., Macduff B.M.,
RA Sato T.A., Maliszewski C.R., Fanslow W.C.;
RT "Recombinant human CD40 ligand stimulates B cell proliferation and
RT immunoglobulin E secretion.";
RL J. Exp. Med. 176:1543-1550(1992).
RN [5]
RP NUCLEOTIDE SEQUENCE [MRNA], AND SUBCELLULAR LOCATION.
RX PubMed=7678552; DOI=10.1016/0014-5793(93)81175-y;
RA Gauchat J.-F., Aubry J.-P., Mazzei G.J., Life P., Jomotte T., Elson G.,
RA Bonnefoy J.-Y.;
RT "Human CD40-ligand: molecular cloning, cellular distribution and regulation
RT of expression by factors controlling IgE production.";
RL FEBS Lett. 315:259-266(1993).
RN [6]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=7999797; DOI=10.1016/0167-4781(94)00179-7;
RA Shimadzu M., Nunoi H., Terasaki H., Ninomiya R., Iwata M., Kanegasaka S.,
RA Matsuda I.;
RT "Structural organization of the gene for CD40 ligand: molecular analysis
RT for diagnosis of X-linked hyper-IgM syndrome.";
RL Biochim. Biophys. Acta 1260:67-72(1995).
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Blood;
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 project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [8]
RP PROTEIN SEQUENCE OF 113-117, PROTEOLYTIC PROCESSING, SUBUNIT, AND
RP SUBCELLULAR LOCATION.
RX PubMed=8626375; DOI=10.1074/jbc.271.11.5965;
RA Pietravalle F., Lecoanet-Henchoz S., Blasey H., Aubry J.-P., Elson G.,
RA Edgerton M.D., Bonnefoy J.-Y., Gauchat J.-F.;
RT "Human native soluble CD40L is a biologically active trimer, processed
RT inside microsomes.";
RL J. Biol. Chem. 271:5965-5967(1996).
RN [9]
RP FUNCTION.
RX PubMed=8617933;
RA Blotta M.H., Marshall J.D., DeKruyff R.H., Umetsu D.T.;
RT "Cross-linking of the CD40 ligand on human CD4+ T lymphocytes generates a
RT costimulatory signal that up-regulates IL-4 synthesis.";
RL J. Immunol. 156:3133-3140(1996).
RN [10]
RP GLYCOSYLATION AT ASN-240, STRUCTURE OF CARBOHYDRATE ON ASN-240,
RP IDENTIFICATION BY MASS SPECTROMETRY, AND SUBUNIT.
RX PubMed=11676606; DOI=10.1006/prep.2001.1501;
RA Khandekar S.S., Silverman C., Wells-Marani J., Bacon A.M., Birrell H.,
RA Brigham-Burke M., DeMarini D.J., Jonak Z.L., Camilleri P.,
RA Fishman-Lobell J.;
RT "Determination of carbohydrate structures N-linked to soluble CD154 and
RT characterization of the interactions of CD40 with CD154 expressed in Pichia
RT pastoris and Chinese hamster ovary cells.";
RL Protein Expr. Purif. 23:301-310(2001).
RN [11]
RP FUNCTION.
RX PubMed=15193700; DOI=10.1016/j.jacc.2003.12.055;
RA Furman M.I., Krueger L.A., Linden M.D., Barnard M.R., Frelinger A.L. III,
RA Michelson A.D.;
RT "Release of soluble CD40L from platelets is regulated by glycoprotein
RT IIb/IIIa and actin polymerization.";
RL J. Am. Coll. Cardiol. 43:2319-2325(2004).
RN [12]
RP FUNCTION, AND SUBCELLULAR LOCATION.
RX PubMed=15067037; DOI=10.1084/jem.20031705;
RA Mikolajczak S.A., Ma B.Y., Yoshida T., Yoshida R., Kelvin D.J., Ochi A.;
RT "The modulation of CD40 ligand signaling by transmembrane CD28 splice
RT variant in human T cells.";
RL J. Exp. Med. 199:1025-1031(2004).
RN [13]
RP FUNCTION AS CD40 AND INTEGRIN LIGAND, CHARACTERIZATION OF VARIANTS HIGM1
RP CYS-170; ARG-174; ILE-176; ASP-208; TYR-224; ALA-226; VAL-227 AND SER-258,
RP AND MUTAGENESIS OF TYR-170; HIS-224; GLY-226 AND GLY-252.
RX PubMed=31331973; DOI=10.4049/jimmunol.1801630;
RA Takada Y.K., Yu J., Shimoda M., Takada Y.;
RT "Integrin Binding to the Trimeric Interface of CD40L Plays a Critical Role
RT in CD40/CD40L Signaling.";
RL J. Immunol. 203:1383-1391(2019).
RN [14]
RP X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS) OF 116-261, AND SUBUNIT.
RX PubMed=8589998; DOI=10.1016/s0969-2126(01)00239-8;
RA Karpsusas M., Hsu Y.-M., Wang J.-H., Thompson J., Lederman S., Chess L.,
RA Thomas D.;
RT "2-A crystal structure of an extracellular fragment of human CD40 ligand.";
RL Structure 3:1031-1039(1995).
RN [15]
RP 3D-STRUCTURE MODELING OF COMPLEX WITH CD40.
RX PubMed=9605317; DOI=10.1002/pro.5560070506;
RA Singh J., Garber E., van Vlijmen H., Karpsusas M., Hsu Y.-M., Zheng Z.,
RA Naismith J.H., Thomas D.;
RT "The role of polar interactions in the molecular recognition of CD40L with
RT its receptor CD40.";
RL Protein Sci. 7:1124-1135(1998).
RN [16]
RP VARIANTS HIGM1 ARG-36 AND GLY-140.
RX PubMed=7679206; DOI=10.1038/361539a0;
RA Korthaeuer U., Graf D., Mages H.W., Briere F., Padayachee M., Malcolm S.,
RA Ugazio A.G., Notarangelo L.D., Levinsky R.J., Kroczek R.A.;
RT "Defective expression of T-cell CD40 ligand causes X-linked
RT immunodeficiency with hyper-IgM.";
RL Nature 361:539-541(1993).
RN [17]
RP VARIANT HIGM1 GLU-123.
RX PubMed=8094231; DOI=10.1038/361541a0;
RA Disanto J.P., Bonnefoy J.-Y., Gauchat J.-F., Fischer A.,
RA de Saint Basile G.;
RT "CD40 ligand mutations in X-linked immunodeficiency with hyper-IgM.";
RL Nature 361:541-543(1993).
RN [18]
RP VARIANTS HIGM1 PRO-155; ASN-211 AND VAL-227.
RX PubMed=7679801; DOI=10.1126/science.7679801;
RA Allen R.C., Armitage R.J., Conley M.E., Rosenblatt H., Jenkins N.A.,
RA Copeland N.G., Bedell M.A., Edelhoff S., Disteche C.M., Simoneaux D.K.,
RA Fanslow W.C., Belmont J.W., Spriggs M.K.;
RT "CD40 ligand gene defects responsible for X-linked hyper-IgM syndrome.";
RL Science 259:990-993(1993).
RN [19]
RP VARIANTS HIGM1 ALA-126; ARG-140 AND GLU-144.
RX PubMed=7717401;
RA Macchi P., Villa A., Strina D., Sacco M.G., Morali F., Brugnoni D.,
RA Giliani S., Mantuano E., Fasth A., Andersson B., Zegers B.J.M., Cavagni G.,
RA Reznick I., Levy J., Zan-Bar I., Porat Y., Airo P., Plebani A., Vezzoni P.,
RA Notarangelo L.D.;
RT "Characterization of nine novel mutations in the CD40 ligand gene in
RT patients with X-linked hyper IgM syndrome of various ancestry.";
RL Am. J. Hum. Genet. 56:898-906(1995).
RN [20]
RP VARIANT HIGM1 GLU-237.
RX PubMed=7532185; DOI=10.1172/jci117692;
RA Saiki O., Tanaka T., Wada Y., Uda H., Inoue A., Katada Y., Izeki M.,
RA Iwata M., Nunoi H., Matsuda I.;
RT "Signaling through CD40 rescues IgE but not IgG or IgA secretion in X-
RT linked immunodeficiency with hyper-IgM.";
RL J. Clin. Invest. 95:510-514(1995).
RN [21]
RP VARIANTS HIGM1 ARG-38; ARG-125; ARG-174 AND SER-257.
RX PubMed=8889581;
RX DOI=10.1002/(sici)1098-1004(1996)8:3<223::aid-humu5>3.0.co;2-a;
RA Katz F., Hinshelwood S., Rutland P., Jones A., Kinnon C., Morgan G.;
RT "Mutation analysis in CD40 ligand deficiency leading to X-linked
RT hypogammaglobulinemia with hyper IgM syndrome.";
RL Hum. Mutat. 8:223-228(1996).
RN [22]
RP VARIANTS HIGM1 PRO-155 AND VAL-227, AND VARIANT ARG-219.
RX PubMed=8550833; DOI=10.1172/jci118389;
RA Lin Q., Rohrer J., Allen R.C., Larche M., Greene J.M., Shigeoka A.O.,
RA Gatti R.A., Derauf D.C., Belmont J.W., Conley M.E.;
RT "A single strand conformation polymorphism study of CD40 ligand. Efficient
RT mutation analysis and carrier detection for X-linked hyper IgM syndrome.";
RL J. Clin. Invest. 97:196-201(1996).
RN [23]
RP VARIANTS HIGM1 ARG-36; CYS-140; GLY-227 DEL; SER-231 AND MET-254.
RX PubMed=9150729; DOI=10.1007/s004390050417;
RA Nonoyama S., Shimadzu M., Toru H., Seyama K., Nunoi H., Neubauer M.,
RA Yata J., Och H.D.;
RT "Mutations of the CD40 ligand gene in 13 Japanese patients with X-linked
RT hyper-IgM syndrome.";
RL Hum. Genet. 99:624-627(1997).
RN [24]
RP VARIANTS HIGM1 SER-116; ASN-147; CYS-170; VAL-227; SER-231; PRO-235;
RP MET-254 AND SER-258.
RX PubMed=9746782;
RA Seyama K., Nonoyama S., Gangsaas I., Hollenbaugh D., Pabst H.F., Aruffo A.,
RA Ochs H.D.;
RT "Mutations of the CD40 ligand gene and its effect on CD40 ligand expression
RT in patients with X-linked hyper IgM syndrome.";
RL Blood 92:2421-2434(1998).
RN [25]
RP VARIANT HIGM1 SER-116.
RX PubMed=26545377; DOI=10.1007/s00251-015-0878-6;
RA Ouadani H., Ben-Mustapha I., Ben-ali M., Ben-khemis L., Largueche B.,
RA Boussoffara R., Maalej S., Fetni I., Hassayoun S., Mahfoudh A.,
RA Mellouli F., Yalaoui S., Masmoudi H., Bejaoui M., Barbouche M.R.;
RT "Novel and recurrent AID mutations underlie prevalent autosomal recessive
RT form of HIGM in consanguineous patients.";
RL Immunogenetics 68:19-28(2016).
CC -!- FUNCTION: Cytokine that acts as a ligand to CD40/TNFRSF5
CC (PubMed:1280226, PubMed:31331973). Costimulates T-cell proliferation
CC and cytokine production (PubMed:8617933). Its cross-linking on T-cells
CC generates a costimulatory signal which enhances the production of IL4
CC and IL10 in conjunction with the TCR/CD3 ligation and CD28
CC costimulation (PubMed:8617933). Induces the activation of NF-kappa-B
CC (PubMed:15067037, PubMed:31331973). Induces the activation of kinases
CC MAPK8 and PAK2 in T-cells (PubMed:15067037). Induces tyrosine
CC phosphorylation of isoform 3 of CD28 (PubMed:15067037). Mediates B-cell
CC proliferation in the absence of co-stimulus as well as IgE production
CC in the presence of IL4 (By similarity). Involved in immunoglobulin
CC class switching (By similarity). {ECO:0000250|UniProtKB:P27548,
CC ECO:0000269|PubMed:1280226, ECO:0000269|PubMed:15067037,
CC ECO:0000269|PubMed:31331973, ECO:0000269|PubMed:8617933}.
CC -!- FUNCTION: [CD40 ligand, soluble form]: Acts as a ligand for integrins,
CC specifically ITGA5:ITGB1 and ITGAV:ITGB3; both integrins and the CD40
CC receptor are required for activation of CD40-CD40LG signaling, which
CC have cell-type dependent effects, such as B-cell activation, NF-kappa-B
CC signaling and anti-apoptotic signaling. {ECO:0000269|PubMed:31331973}.
CC -!- SUBUNIT: Homotrimer (PubMed:8626375, PubMed:11676606, PubMed:8589998).
CC Interacts with isoform 3 of CD28 (PubMed:15067037). CD40 ligand,
CC soluble form: Exists as either a monomer or a homotrimer
CC (PubMed:8626375, PubMed:31331973). Forms a ternary complex between CD40
CC and integrins for CD40-CD40LG signaling (PubMed:31331973).
CC {ECO:0000269|PubMed:11676606, ECO:0000269|PubMed:15067037,
CC ECO:0000269|PubMed:31331973, ECO:0000269|PubMed:8589998,
CC ECO:0000269|PubMed:8626375}.
CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:8626375};
CC Single-pass type II membrane protein {ECO:0000303|PubMed:8626375}. Cell
CC surface {ECO:0000269|PubMed:15067037, ECO:0000269|PubMed:7678552}.
CC -!- SUBCELLULAR LOCATION: [CD40 ligand, soluble form]: Secreted
CC {ECO:0000269|PubMed:8626375}. Note=Release of soluble CD40L from
CC platelets is partially regulated by GP IIb/IIIa, actin polymerization,
CC and a matrix metalloproteinases (MMP) inhibitor-sensitive pathway.
CC {ECO:0000269|PubMed:15193700}.
CC -!- TISSUE SPECIFICITY: Specifically expressed on activated CD4+ T-
CC lymphocytes.
CC -!- PTM: The soluble form derives from the membrane form by proteolytic
CC processing. {ECO:0000269|PubMed:8626375}.
CC -!- PTM: N-linked glycan is a mixture of high mannose and complex type.
CC Glycan structure does not influence binding affinity to CD40.
CC {ECO:0000269|PubMed:11676606}.
CC -!- PTM: Not O-glycosylated.
CC -!- DISEASE: Immunodeficiency with hyper-IgM, type 1 (HIGM1) [MIM:308230]:
CC Immunoglobulin isotype switch defect characterized by elevated
CC concentrations of serum IgM and decreased amounts of all other
CC isotypes. Affected males present at an early age (usually within the
CC first year of life) recurrent bacterial and opportunistic infections,
CC including Pneumocystis carinii pneumonia and intractable diarrhea due
CC to cryptosporidium infection. Despite substitution treatment with
CC intravenous immunoglobulin, the overall prognosis is rather poor, with
CC a death rate of about 10% before adolescence.
CC {ECO:0000269|PubMed:26545377, ECO:0000269|PubMed:31331973,
CC ECO:0000269|PubMed:7532185, ECO:0000269|PubMed:7678782,
CC ECO:0000269|PubMed:7679206, ECO:0000269|PubMed:7679801,
CC ECO:0000269|PubMed:7717401, ECO:0000269|PubMed:8094231,
CC ECO:0000269|PubMed:8550833, ECO:0000269|PubMed:8889581,
CC ECO:0000269|PubMed:9150729, ECO:0000269|PubMed:9746782}. Note=The
CC disease is caused by variants affecting the gene represented in this
CC entry.
CC -!- SIMILARITY: Belongs to the tumor necrosis factor family. {ECO:0000305}.
CC -!- WEB RESOURCE: Name=CD40Lbase; Note=CD40L defect database;
CC URL="http://structure.bmc.lu.se/idbase/CD40Lbase/";
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DR EMBL; X68550; CAA48554.1; -; mRNA.
DR EMBL; Z15017; CAA78737.1; -; mRNA.
DR EMBL; X67878; CAA48077.1; -; mRNA.
DR EMBL; L07414; AAA35662.1; -; mRNA.
DR EMBL; D31797; BAA06599.1; -; Genomic_DNA.
DR EMBL; BC071754; AAH71754.1; -; mRNA.
DR EMBL; BC074950; AAH74950.1; -; mRNA.
DR CCDS; CCDS14659.1; -.
DR PIR; S28017; I53476.
DR RefSeq; NP_000065.1; NM_000074.2.
DR PDB; 1ALY; X-ray; 2.00 A; A=116-261.
DR PDB; 1I9R; X-ray; 3.10 A; A/B/C=116-261.
DR PDB; 3LKJ; X-ray; 2.50 A; A/B/C=121-261.
DR PDB; 3QD6; X-ray; 3.50 A; A/B/C/D/E/F=116-261.
DR PDB; 6BRB; X-ray; 2.82 A; A=120-261.
DR PDB; 6W9G; X-ray; 1.82 A; A/B/C=116-261.
DR PDB; 7SGM; X-ray; 2.00 A; A/B/C=116-261.
DR PDBsum; 1ALY; -.
DR PDBsum; 1I9R; -.
DR PDBsum; 3LKJ; -.
DR PDBsum; 3QD6; -.
DR PDBsum; 6BRB; -.
DR PDBsum; 6W9G; -.
DR PDBsum; 7SGM; -.
DR AlphaFoldDB; P29965; -.
DR SMR; P29965; -.
DR BioGRID; 107397; 10.
DR DIP; DIP-3013N; -.
DR STRING; 9606.ENSP00000359663; -.
DR BindingDB; P29965; -.
DR ChEMBL; CHEMBL3580491; -.
DR DrugBank; DB06475; Ruplizumab.
DR GlyConnect; 610; 12 N-Linked glycans.
DR GlyGen; P29965; 2 sites, 32 N-linked glycans (2 sites).
DR iPTMnet; P29965; -.
DR PhosphoSitePlus; P29965; -.
DR BioMuta; CD40LG; -.
DR DMDM; 231718; -.
DR MassIVE; P29965; -.
DR MaxQB; P29965; -.
DR PaxDb; P29965; -.
DR PeptideAtlas; P29965; -.
DR PRIDE; P29965; -.
DR ProteomicsDB; 54611; -.
DR ABCD; P29965; 6 sequenced antibodies.
DR Antibodypedia; 16693; 1981 antibodies from 48 providers.
DR DNASU; 959; -.
DR Ensembl; ENST00000370629.7; ENSP00000359663.2; ENSG00000102245.8.
DR GeneID; 959; -.
DR KEGG; hsa:959; -.
DR MANE-Select; ENST00000370629.7; ENSP00000359663.2; NM_000074.3; NP_000065.1.
DR UCSC; uc004faa.4; human.
DR CTD; 959; -.
DR DisGeNET; 959; -.
DR GeneCards; CD40LG; -.
DR GeneReviews; CD40LG; -.
DR HGNC; HGNC:11935; CD40LG.
DR HPA; ENSG00000102245; Tissue enhanced (lymphoid).
DR MalaCards; CD40LG; -.
DR MIM; 300386; gene.
DR MIM; 308230; phenotype.
DR neXtProt; NX_P29965; -.
DR OpenTargets; ENSG00000102245; -.
DR Orphanet; 101088; X-linked hyper-IgM syndrome.
DR PharmGKB; PA36626; -.
DR VEuPathDB; HostDB:ENSG00000102245; -.
DR eggNOG; KOG3656; Eukaryota.
DR GeneTree; ENSGT01050000244878; -.
DR InParanoid; P29965; -.
DR OMA; YLHIPKE; -.
DR OrthoDB; 1146113at2759; -.
DR PhylomeDB; P29965; -.
DR TreeFam; TF332169; -.
DR PathwayCommons; P29965; -.
DR Reactome; R-HSA-198933; Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell.
DR Reactome; R-HSA-5668541; TNFR2 non-canonical NF-kB pathway.
DR Reactome; R-HSA-5676594; TNF receptor superfamily (TNFSF) members mediating non-canonical NF-kB pathway.
DR SignaLink; P29965; -.
DR SIGNOR; P29965; -.
DR BioGRID-ORCS; 959; 5 hits in 696 CRISPR screens.
DR EvolutionaryTrace; P29965; -.
DR GeneWiki; CD154; -.
DR GenomeRNAi; 959; -.
DR Pharos; P29965; Tbio.
DR PRO; PR:P29965; -.
DR Proteomes; UP000005640; Chromosome X.
DR RNAct; P29965; protein.
DR Bgee; ENSG00000102245; Expressed in granulocyte and 90 other tissues.
DR ExpressionAtlas; P29965; baseline and differential.
DR Genevisible; P29965; HS.
DR GO; GO:0009986; C:cell surface; IDA:UniProtKB.
DR GO; GO:0009897; C:external side of plasma membrane; IEA:Ensembl.
DR GO; GO:0005615; C:extracellular space; IEA:UniProtKB-KW.
DR GO; GO:0005794; C:Golgi apparatus; IDA:HPA.
DR GO; GO:0016021; C:integral component of membrane; NAS:UniProtKB.
DR GO; GO:0005887; C:integral component of plasma membrane; TAS:ProtInc.
DR GO; GO:0005886; C:plasma membrane; IDA:HPA.
DR GO; GO:0005174; F:CD40 receptor binding; IMP:UniProtKB.
DR GO; GO:0005125; F:cytokine activity; IEA:UniProtKB-KW.
DR GO; GO:0005178; F:integrin binding; IMP:UniProtKB.
DR GO; GO:0043539; F:protein serine/threonine kinase activator activity; IDA:UniProtKB.
DR GO; GO:0005164; F:tumor necrosis factor receptor binding; IEA:InterPro.
DR GO; GO:0030183; P:B cell differentiation; IEA:Ensembl.
DR GO; GO:0042100; P:B cell proliferation; IDA:UniProtKB.
DR GO; GO:0023035; P:CD40 signaling pathway; IMP:UniProtKB.
DR GO; GO:0006954; P:inflammatory response; IDA:UniProtKB.
DR GO; GO:0007229; P:integrin-mediated signaling pathway; IMP:UniProtKB.
DR GO; GO:0045190; P:isotype switching; ISS:UniProtKB.
DR GO; GO:0007159; P:leukocyte cell-cell adhesion; NAS:UniProtKB.
DR GO; GO:0043066; P:negative regulation of apoptotic process; IDA:UniProtKB.
DR GO; GO:0030168; P:platelet activation; IDA:UniProtKB.
DR GO; GO:2000353; P:positive regulation of endothelial cell apoptotic process; IDA:BHF-UCL.
DR GO; GO:0032733; P:positive regulation of interleukin-10 production; IDA:UniProtKB.
DR GO; GO:0032735; P:positive regulation of interleukin-12 production; IDA:UniProtKB.
DR GO; GO:0032753; P:positive regulation of interleukin-4 production; IDA:UniProtKB.
DR GO; GO:0051092; P:positive regulation of NF-kappaB transcription factor activity; IDA:UniProtKB.
DR GO; GO:0042102; P:positive regulation of T cell proliferation; IDA:UniProtKB.
DR GO; GO:0002637; P:regulation of immunoglobulin production; IEA:Ensembl.
DR GO; GO:0031295; P:T cell costimulation; TAS:UniProtKB.
DR CDD; cd00184; TNF; 1.
DR Gene3D; 2.60.120.40; -; 1.
DR InterPro; IPR003263; CD40L.
DR InterPro; IPR021184; TNF_CS.
DR InterPro; IPR006052; TNF_dom.
DR InterPro; IPR008983; Tumour_necrosis_fac-like_dom.
DR PANTHER; PTHR11471:SF5; PTHR11471:SF5; 1.
DR Pfam; PF00229; TNF; 1.
DR PIRSF; PIRSF016527; TNF_5; 1.
DR PRINTS; PR01702; CD40LIGAND.
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; Cell membrane; Cytokine; Direct protein sequencing;
KW Disease variant; Disulfide bond; Glycoprotein; Membrane;
KW Reference proteome; Secreted; Signal-anchor; Transmembrane;
KW Transmembrane helix.
FT CHAIN 1..261
FT /note="CD40 ligand, membrane form"
FT /id="PRO_0000034484"
FT CHAIN 113..261
FT /note="CD40 ligand, soluble form"
FT /evidence="ECO:0000269|PubMed:8626375"
FT /id="PRO_0000034485"
FT TOPO_DOM 1..22
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 23..46
FT /note="Helical; Signal-anchor for type II membrane protein"
FT /evidence="ECO:0000255"
FT TOPO_DOM 47..261
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT SITE 112..113
FT /note="Cleavage"
FT CARBOHYD 240
FT /note="N-linked (GlcNAc...) (complex) asparagine;
FT alternate"
FT /evidence="ECO:0000269|PubMed:11676606"
FT CARBOHYD 240
FT /note="N-linked (GlcNAc...) (high mannose) asparagine;
FT alternate"
FT /evidence="ECO:0000269|PubMed:11676606"
FT DISULFID 178..218
FT /evidence="ECO:0000255"
FT VARIANT 36
FT /note="M -> R (in HIGM1; dbSNP:rs104894774)"
FT /evidence="ECO:0000269|PubMed:7679206,
FT ECO:0000269|PubMed:9150729"
FT /id="VAR_007513"
FT VARIANT 38
FT /note="G -> R (in HIGM1)"
FT /evidence="ECO:0000269|PubMed:8889581"
FT /id="VAR_017925"
FT VARIANT 116
FT /note="G -> R (in HIGM1)"
FT /id="VAR_017929"
FT VARIANT 116
FT /note="G -> S (in HIGM1)"
FT /evidence="ECO:0000269|PubMed:26545377,
FT ECO:0000269|PubMed:9746782"
FT /id="VAR_017930"
FT VARIANT 123
FT /note="A -> E (in HIGM1; dbSNP:rs104894778)"
FT /evidence="ECO:0000269|PubMed:8094231"
FT /id="VAR_007514"
FT VARIANT 125
FT /note="H -> R (in HIGM1)"
FT /evidence="ECO:0000269|PubMed:8889581"
FT /id="VAR_017926"
FT VARIANT 126
FT /note="V -> A (in HIGM1)"
FT /evidence="ECO:0000269|PubMed:7717401"
FT /id="VAR_007515"
FT VARIANT 126
FT /note="V -> D (in HIGM1)"
FT /id="VAR_017931"
FT VARIANT 128..129
FT /note="SE -> RG (in HIGM1)"
FT /id="VAR_007516"
FT VARIANT 140
FT /note="W -> C (in HIGM1)"
FT /evidence="ECO:0000269|PubMed:9150729"
FT /id="VAR_007517"
FT VARIANT 140
FT /note="W -> G (in HIGM1; dbSNP:rs104894777)"
FT /evidence="ECO:0000269|PubMed:7679206"
FT /id="VAR_007518"
FT VARIANT 140
FT /note="W -> R (in HIGM1)"
FT /evidence="ECO:0000269|PubMed:7717401"
FT /id="VAR_007519"
FT VARIANT 143
FT /note="K -> T (in HIGM1)"
FT /id="VAR_017932"
FT VARIANT 144
FT /note="G -> E (in HIGM1; dbSNP:rs886039326)"
FT /evidence="ECO:0000269|PubMed:7717401"
FT /id="VAR_007520"
FT VARIANT 147
FT /note="T -> N (in HIGM1; dbSNP:rs1057521127)"
FT /evidence="ECO:0000269|PubMed:9746782"
FT /id="VAR_017922"
FT VARIANT 155
FT /note="L -> P (in HIGM1; dbSNP:rs104894769)"
FT /evidence="ECO:0000269|PubMed:7679801,
FT ECO:0000269|PubMed:8550833"
FT /id="VAR_007521"
FT VARIANT 170
FT /note="Y -> C (in HIGM1; decreases ITGA5:ITGB1 and
FT ITGAV:ITGB3 binding of the soluble form; decreases
FT activation of NF-kappa-B signaling; slightly decreases CD40
FT binding of the soluble form; dbSNP:rs756468554)"
FT /evidence="ECO:0000269|PubMed:31331973,
FT ECO:0000269|PubMed:9746782"
FT /id="VAR_017923"
FT VARIANT 173
FT /note="A -> D (in HIGM1)"
FT /id="VAR_017933"
FT VARIANT 174
FT /note="Q -> R (in HIGM1; decreases ITGA5:ITGB1 and
FT ITGAV:ITGB3 binding of the soluble form; decreases
FT activation of NF-kappa-B signaling)"
FT /evidence="ECO:0000269|PubMed:31331973,
FT ECO:0000269|PubMed:8889581"
FT /id="VAR_017927"
FT VARIANT 176
FT /note="T -> I (in HIGM1; decreases ITGA5:ITGB1 and
FT ITGAV:ITGB3 binding of the soluble form; decreases
FT activation of NF-kappa-B signaling)"
FT /evidence="ECO:0000269|PubMed:31331973"
FT /id="VAR_017934"
FT VARIANT 195
FT /note="L -> P (in HIGM1)"
FT /id="VAR_017935"
FT VARIANT 208
FT /note="A -> D (in HIGM1; decreases ITGA5:ITGB1 and
FT ITGAV:ITGB3 binding of the soluble form; decreases
FT activation of NF-kappa-B signaling)"
FT /evidence="ECO:0000269|PubMed:31331973"
FT /id="VAR_017936"
FT VARIANT 211
FT /note="T -> N (in HIGM1; dbSNP:rs1569377829)"
FT /evidence="ECO:0000269|PubMed:7679801"
FT /id="VAR_007522"
FT VARIANT 219
FT /note="G -> R (in dbSNP:rs148594123)"
FT /evidence="ECO:0000269|PubMed:8550833"
FT /id="VAR_007523"
FT VARIANT 224
FT /note="H -> Y (in HIGM1; no effect on ITGA5:ITGB1 and
FT ITGAV:ITGB3 binding of the soluble form; increases NF-
FT kappa-B signaling)"
FT /evidence="ECO:0000269|PubMed:31331973"
FT /id="VAR_017937"
FT VARIANT 226
FT /note="G -> A (in HIGM1; no effect on ITGA5:ITGB1 and
FT ITGAV:ITGB3 binding of the soluble form; slightly increases
FT NF-kappa-B signaling)"
FT /evidence="ECO:0000269|PubMed:31331973"
FT /id="VAR_017938"
FT VARIANT 227
FT /note="G -> V (in HIGM1; decreases ITGA5:ITGB1 and
FT ITGAV:ITGB3 binding of the soluble form; decreases
FT activation of NF-kappa-B signaling; dbSNP:rs104894768)"
FT /evidence="ECO:0000269|PubMed:31331973,
FT ECO:0000269|PubMed:7679801, ECO:0000269|PubMed:8550833,
FT ECO:0000269|PubMed:9746782"
FT /id="VAR_007524"
FT VARIANT 227
FT /note="Missing (in HIGM1)"
FT /evidence="ECO:0000269|PubMed:9150729"
FT /id="VAR_007525"
FT VARIANT 231
FT /note="L -> S (in HIGM1)"
FT /evidence="ECO:0000269|PubMed:9150729,
FT ECO:0000269|PubMed:9746782"
FT /id="VAR_007526"
FT VARIANT 235
FT /note="A -> P (in HIGM1; dbSNP:rs104894771)"
FT /evidence="ECO:0000269|PubMed:7678782,
FT ECO:0000269|PubMed:9746782"
FT /id="VAR_007527"
FT VARIANT 237
FT /note="V -> E (in HIGM1)"
FT /evidence="ECO:0000269|PubMed:7532185"
FT /id="VAR_017939"
FT VARIANT 254
FT /note="T -> M (in HIGM1; dbSNP:rs193922136)"
FT /evidence="ECO:0000269|PubMed:9150729,
FT ECO:0000269|PubMed:9746782"
FT /id="VAR_007528"
FT VARIANT 257
FT /note="G -> D (in HIGM1; dbSNP:rs1477466218)"
FT /id="VAR_017940"
FT VARIANT 257
FT /note="G -> S (in HIGM1)"
FT /evidence="ECO:0000269|PubMed:8889581"
FT /id="VAR_017928"
FT VARIANT 258
FT /note="L -> S (in HIGM1; decreases ITGA5:ITGB1 and
FT ITGAV:ITGB3 binding of the soluble form; decreases
FT activation of NF-kappa-B signaling; dbSNP:rs1569377884)"
FT /evidence="ECO:0000269|PubMed:31331973,
FT ECO:0000269|PubMed:9746782"
FT /id="VAR_017924"
FT MUTAGEN 170
FT /note="Y->E: Decreases ITGA5:ITGB1 binding, B-cell
FT activation, activation of NF-kappa-B signaling, and anti-
FT apoptotic signaling; in soluble form. Slightly decreases
FT CD40 binding; in soluble form."
FT /evidence="ECO:0000269|PubMed:31331973"
FT MUTAGEN 224
FT /note="H->E: Decreases ITGA5:ITGB1 binding, B-cell
FT activation, activation of NF-kappa-B signaling, and anti-
FT apoptotic signaling; when associated with E-226 in soluble
FT form. No effect on CD40 binding; when associated with E-226
FT in soluble form."
FT /evidence="ECO:0000269|PubMed:31331973"
FT MUTAGEN 226
FT /note="G->E: Decreases ITGA5:ITGB1 binding, B-cell
FT activation, activation of NF-kappa-B signaling, and anti-
FT apoptotic signaling; when associated with E-224 in soluble
FT form. No effect on CD40 binding; when associated with E-224
FT in soluble form."
FT /evidence="ECO:0000269|PubMed:31331973"
FT MUTAGEN 252
FT /note="G->E: Decreases ITGA5:ITGB1 binding, B-cell
FT activation, activation of NF-kappa-B signaling, and anti-
FT apoptotic signaling; in soluble form. No effect on CD40
FT binding; in soluble form."
FT /evidence="ECO:0000269|PubMed:31331973"
FT STRAND 123..129
FT /evidence="ECO:0007829|PDB:6W9G"
FT STRAND 132..134
FT /evidence="ECO:0007829|PDB:1ALY"
FT STRAND 135..137
FT /evidence="ECO:0007829|PDB:6BRB"
FT STRAND 139..142
FT /evidence="ECO:0007829|PDB:6W9G"
FT STRAND 153..156
FT /evidence="ECO:0007829|PDB:6W9G"
FT TURN 157..159
FT /evidence="ECO:0007829|PDB:6W9G"
FT STRAND 160..165
FT /evidence="ECO:0007829|PDB:6W9G"
FT STRAND 167..179
FT /evidence="ECO:0007829|PDB:6W9G"
FT TURN 181..183
FT /evidence="ECO:0007829|PDB:1ALY"
FT STRAND 189..196
FT /evidence="ECO:0007829|PDB:6W9G"
FT STRAND 203..210
FT /evidence="ECO:0007829|PDB:6W9G"
FT STRAND 219..231
FT /evidence="ECO:0007829|PDB:6W9G"
FT STRAND 236..242
FT /evidence="ECO:0007829|PDB:6W9G"
FT HELIX 244..246
FT /evidence="ECO:0007829|PDB:6W9G"
FT STRAND 253..260
FT /evidence="ECO:0007829|PDB:6W9G"
SQ SEQUENCE 261 AA; 29274 MW; 16F5CEB093BCC2BB CRC64;
MIETYNQTSP RSAATGLPIS MKIFMYLLTV FLITQMIGSA LFAVYLHRRL DKIEDERNLH
EDFVFMKTIQ RCNTGERSLS LLNCEEIKSQ FEGFVKDIML NKEETKKENS FEMQKGDQNP
QIAAHVISEA SSKTTSVLQW AEKGYYTMSN NLVTLENGKQ LTVKRQGLYY IYAQVTFCSN
REASSQAPFI ASLCLKSPGR FERILLRAAN THSSAKPCGQ QSIHLGGVFE LQPGASVFVN
VTDPSQVSHG TGFTSFGLLK L
