P29965 (CD40L_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

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:

1. CD40 ligand, membrane form
2. CD40 ligand, soluble form

Gene names

Name:	CD40LG
Synonyms:	CD40L, TNFSF5, TRAP

Organism

Homo sapiens (Human) [Reference proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Primates › Haplorrhini › Simiiformes › Catarrhini › Hominoidea › Hominidae › Homininae › Homo

Protein attributes

Sequence length	261 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	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 component	Cell membrane Membrane Secreted
Coding sequence diversity	Polymorphism
Disease	Disease mutation
Domain	Signal-anchor Transmembrane Transmembrane helix
Molecular function	Cytokine
PTM	Disulfide bond Glycoprotein Phosphoprotein
Technical term	3D-structure Complete proteome Direct protein sequencing Reference proteome
Gene Ontology (GO)
Biological_process	B cell differentiation Inferred from electronic annotation. Source: Compara B cell proliferation Inferred from direct assay PubMed 8605945. Source: UniProtKB immunoglobulin secretion Inferred from electronic annotation. Source: Compara 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: Compara
Cellular_component	external side of plasma membrane Inferred from electronic annotation. Source: Compara extracellular space Inferred from electronic annotation. Source: UniProtKB-KW integral to plasma membrane Traceable author statement Ref.5. Source: ProtInc
Complete GO annotation...

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 261

261

CD40 ligand, membrane form

PRO_0000034484

Chain

113 – 261

149

CD40 ligand, soluble form

PRO_0000034485

Regions

Topological domain

1 – 22

22

Cytoplasmic Potential

Transmembrane

23 – 46

24

Helical; Signal-anchor for type II membrane protein; Potential

Topological domain

47 – 261

215

Extracellular Potential

Sites

Site

112 – 113

2

Cleavage

Amino acid modifications

Modified residue

4

1

Phosphothreonine By similarity

Glycosylation

240

1

N-linked (GlcNAc...) (high mannose and complex)

CAR_000229

Disulfide bond

178 ↔ 218

Potential

Natural variations

Natural variant

36

1

M → R in HIGM1. Ref.13 Ref.20

VAR_007513

Natural variant

38

1

G → R in HIGM1. Ref.18

VAR_017925

Natural variant

116

1

G → R in HIGM1.

VAR_017929

Natural variant

116

1

G → S in HIGM1. Ref.21

VAR_017930

Natural variant

123

1

A → E in HIGM1. Ref.14

VAR_007514

Natural variant

125

1

H → R in HIGM1. Ref.18

VAR_017926

Natural variant

126

1

V → A in HIGM1. Ref.16

VAR_007515

Natural variant

126

1

V → D in HIGM1.

VAR_017931

Natural variant

128 – 129

2

SE → RG in HIGM1.

VAR_007516

Natural variant

140

1

W → C in HIGM1. Ref.20

VAR_007517

Natural variant

140

1

W → G in HIGM1. Ref.13

VAR_007518

Natural variant

140

1

W → R in HIGM1. Ref.16

VAR_007519

Natural variant

143

1

K → T in HIGM1.

VAR_017932

Natural variant

144

1

G → E in HIGM1. Ref.16

VAR_007520

Natural variant

147

1

T → N in HIGM1. Ref.21

VAR_017922

Natural variant

155

1

L → P in HIGM1. Ref.15 Ref.19

VAR_007521

Natural variant

170

1

Y → C in HIGM1. Ref.21

VAR_017923

Natural variant

173

1

A → D in HIGM1.

VAR_017933

Natural variant

174

1

Q → R in HIGM1. Ref.18

VAR_017927

Natural variant

176

1

T → I in HIGM1.

VAR_017934

Natural variant

195

1

L → P in HIGM1.

VAR_017935

Natural variant

208

1

A → D in HIGM1.

VAR_017936

Natural variant

211

1

T → N in HIGM1. Ref.15

VAR_007522

Natural variant

219

1

G → R. Ref.19

VAR_007523

Natural variant

224

1

H → Y in HIGM1.

VAR_017937

Natural variant

226

1

G → A in HIGM1.

VAR_017938

Natural variant

227

1

G → V in HIGM1. Ref.15 Ref.19 Ref.21

VAR_007524

Natural variant

227

1

Missing in HIGM1. Ref.20

VAR_007525

Natural variant

231

1

L → S in HIGM1. Ref.20 Ref.21

VAR_007526

Natural variant

235

1

A → P in HIGM1. Ref.3 Ref.21

VAR_007527

Natural variant

237

1

V → E in HIGM1. Ref.17

VAR_017939

Natural variant

254

1

T → M in HIGM1. Ref.20 Ref.21

VAR_007528

Natural variant

257

1

G → D in HIGM1.

VAR_017940

Natural variant

257

1

G → S in HIGM1. Ref.18

VAR_017928

Natural variant

258

1

L → S in HIGM1. Ref.21

VAR_017924

Secondary structure

1

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

261

Helix Strand Turn

Details...

Beta strand

123 – 128

6

Beta strand

132 – 134

3

Beta strand

140 – 142

3

Beta strand

153 – 156

4

Turn

157 – 159

3

Beta strand

160 – 165

6

Beta strand

167 – 179

13

Turn

181 – 183

3

Beta strand

186 – 195

10

Beta strand

203 – 211

9

Beta strand

218 – 232

15

Beta strand

237 – 242

6

Helix

244 – 246

3

Beta strand

251 – 260

10

Sequences

	Sequence		Length	Mass (Da)
	P29965 [UniParc]. Last modified April 1, 1993. Version 1. Checksum: 16F5CEB093BCC2BB	FASTA	261	29,274
	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

References

	« Hide 'large scale' referencesShow '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, 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.

IPI

IPI00024686.

PIR

I53476. S28017.

RefSeq

NP_000065.1. NM_000074.2.

UniGene

Hs.592244.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
1ALY	X-ray	2.00	A	116-261	[»]
1I9R	X-ray	3.10	A/B/C	116-261	[»]
3LKJ	X-ray	2.50	A/B/C	121-261	[»]
3QD6	X-ray	3.50	A/B/C/D/E/F	116-261	[»]

ProteinModelPortal

P29965.

ModBase

Search...

Protein-protein interaction databases

DIP

DIP-3013N.

STRING

9606.ENSP00000359663.

PTM databases

GlycoSuiteDB

P29965.

PhosphoSite

P29965.

Polymorphism databases

DMDM

231718.

Proteomic databases

PaxDb

P29965.

PRIDE

P29965.

Protocols and materials databases

DNASU

959.

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000370629; ENSP00000359663; ENSG00000102245.

GeneID

959.

KEGG

hsa:959.

UCSC

uc004faa.3. human.

Organism-specific databases

CTD

959.

GeneCards

GC0XP135730.

HGNC

HGNC:11935. CD40LG.

HPA

HPA045827.

MIM

300386. gene.
308230. phenotype.

neXtProt

NX_P29965.

Orphanet

101088. X-linked hyper-IgM syndrome.

PharmGKB

PA36626.

GenAtlas

Search...

Phylogenomic databases

eggNOG

NOG39330.

HOGENOM

HOG000111291.

HOVERGEN

HBG079629.

InParanoid

P29965.

KO

K03161.

OMA

KIFMYLL.

OrthoDB

EOG4G4GRV.

PhylomeDB

P29965.

Enzyme and pathway databases

Pathway_Interaction_DB

nfat_tfpathway. Calcineurin-regulated NFAT-dependent transcription in lymphocytes.
tcrcalciumpathway. Calcium signaling in the CD4+ TCR pathway.
il4_2pathway. IL4-mediated signaling events.

Reactome

REACT_6900. Immune System.

Gene expression databases

ArrayExpress

P29965.

Bgee

P29965.

CleanEx

HS_CD40LG.

Genevestigator

P29965.

GermOnline

ENSG00000102245. Homo sapiens.

Family and domain databases

Gene3D

2.60.120.40. 1 hit.

InterPro

IPR006052. TNF.
IPR021184. TNF_CS.
IPR003263. TNF_ligand_5.
IPR008983. Tumour_necrosis_fac-like_dom.
[Graphical view]

Pfam

PF00229. TNF. 1 hit.
[Graphical view]

PIRSF

PIRSF016527. TNF_5. 1 hit.

PRINTS

PR01702. CD40LIGAND.

SMART

SM00207. TNF. 1 hit.
[Graphical view]

SUPFAM

SSF49842. TNF_like. 1 hit.

PROSITE

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

ProtoNet

Search...

Other

DrugBank

DB01076. Atorvastatin.

EvolutionaryTrace

P29965.

GenomeRNAi

959.

NextBio

3996.

PMAP-CutDB

P29965.

SOURCE

Search...

Entry information

Entry name

CD40L_HUMAN

Accession

Primary (citable) accession number: P29965

Entry history

Integrated into UniProtKB/Swiss-Prot:	April 1, 1993
Last sequence update:	April 1, 1993
Last modified:	May 1, 2013
This is version 158 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any 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.