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Protein

Cytotoxic T-lymphocyte protein 4

Gene

CTLA4

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

Inhibitory receptor acting as a major negative regulator of T-cell responses. The affinity of CTLA4 for its natural B7 family ligands, CD80 and CD86, is considerably stronger than the affinity of their cognate stimulatory coreceptor CD28.2 Publications

Miscellaneous

The therapeutic antibody Ipilimumab competes for the binding site of the endogenous ligands CD80/B7-1, CD86/B7-2 and ICOSLG.

GO - Biological processi

  • adaptive immune response Source: UniProtKB-KW
  • B cell receptor signaling pathway Source: UniProtKB
  • cellular response to DNA damage stimulus Source: UniProtKB
  • immune response Source: ProtInc
  • negative regulation of B cell proliferation Source: UniProtKB
  • negative regulation of immune response Source: Ensembl
  • negative regulation of regulatory T cell differentiation Source: BHF-UCL
  • negative regulation of T cell proliferation Source: Ensembl
  • positive regulation of apoptotic process Source: UniProtKB
  • regulation of regulatory T cell differentiation Source: Reactome
  • T cell costimulation Source: Reactome

Keywordsi

Biological processAdaptive immunity, Immunity

Enzyme and pathway databases

ReactomeiR-HSA-389513. CTLA4 inhibitory signaling.
R-HSA-8877330. RUNX1 and FOXP3 control the development of regulatory T lymphocytes (Tregs).
SIGNORiP16410.

Names & Taxonomyi

Protein namesi
Recommended name:
Cytotoxic T-lymphocyte protein 4
Alternative name(s):
Cytotoxic T-lymphocyte-associated antigen 4
Short name:
CTLA-4
CD_antigen: CD152
Gene namesi
Name:CTLA4
Synonyms:CD152
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 2

Organism-specific databases

EuPathDBiHostDB:ENSG00000163599.14.
HGNCiHGNC:2505. CTLA4.

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 domaini36 – 161Extracellular1 PublicationAdd BLAST126
Transmembranei162 – 182HelicalSequence analysisAdd BLAST21
Topological domaini183 – 223CytoplasmicSequence analysisAdd BLAST41

Keywords - Cellular componenti

Cell membrane, Membrane

Pathology & Biotechi

Involvement in diseasei

Systemic lupus erythematosus (SLE)2 Publications
Disease susceptibility is associated with variations affecting the gene represented in this entry.
Disease descriptionA chronic, relapsing, inflammatory, and often febrile multisystemic disorder of connective tissue, characterized principally by involvement of the skin, joints, kidneys and serosal membranes. It is of unknown etiology, but is thought to represent a failure of the regulatory mechanisms of the autoimmune system. The disease is marked by a wide range of system dysfunctions, an elevated erythrocyte sedimentation rate, and the formation of LE cells in the blood or bone marrow.
See also OMIM:152700
Genetic variations in CTLA4 may influence susceptibility to Graves disease, an autoimmune disorder associated with overactivity of the thyroid gland and hyperthyroidism.1 Publication
Diabetes mellitus, insulin-dependent, 12 (IDDM12)1 Publication
Disease susceptibility is associated with variations affecting the gene represented in this entry.
Disease descriptionA multifactorial disorder of glucose homeostasis that is characterized by susceptibility to ketoacidosis in the absence of insulin therapy. Clinical features are polydipsia, polyphagia and polyuria which result from hyperglycemia-induced osmotic diuresis and secondary thirst. These derangements result in long-term complications that affect the eyes, kidneys, nerves, and blood vessels.
See also OMIM:601388
Celiac disease 3 (CELIAC3)2 Publications
Disease susceptibility is associated with variations affecting the gene represented in this entry.
Disease descriptionA multifactorial, chronic disorder of the small intestine caused by intolerance to gluten. It is characterized by immune-mediated enteropathy associated with failed intestinal absorption, and malnutrition. In predisposed individuals, the ingestion of gluten-containing food such as wheat and rye induces a flat jejunal mucosa with infiltration of lymphocytes.
See also OMIM:609755
Autoimmune lymphoproliferative syndrome 5 (ALPS5)2 Publications
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionAn autosomal dominant primary immunodeficiency characterized by severe autoimmunity, infiltration of non-lymphoid organs, such as the intestine, lungs and brain, by hyperactive T cells and B cells, autoimmune cytopenias, and hypogammaglobulinemia in early childhood.
See also OMIM:616100
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_07268170R → W in ALPS5. 1 PublicationCorresponds to variant dbSNP:rs606231422Ensembl.1

Pharmaceutical usei

Engineered fusion proteins consisting of the extracellular domain of CTLA4 and the IgG Fc region (Ctla4-Ig), inhibit T-cell-dependent antibody responses, and are used as immunosuppressive agents. They are soluble, have an enhanced affinity for B7 ligands and act as a competitive inhibitor of CD28.

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi45V → D: Strongly reduced interaction with CD80, CD86 and ICOSLG. 1 Publication1
Mutagenesisi47L → D: Strongly reduced interaction with CD80, CD86 and ICOSLG. 1 Publication1
Mutagenesisi49S → A: Strongly reduced interaction with CD80, CD86 and ICOSLG. 1 Publication1
Mutagenesisi70R → A or D: Strongly reduced interaction with CD80, CD86 and ICOSLG. 1 Publication1
Mutagenesisi130K → A or D: Strongly reduced interaction with CD80, CD86 and ICOSLG. 1 Publication1
Mutagenesisi132E → A or R: Strongly reduced interaction with CD80, CD86 and ICOSLG. 1 Publication1
Mutagenesisi139Y → A or D: Strongly reduced interaction with CD80, CD86 and ICOSLG. 1 Publication1
Mutagenesisi143I → A or D: Strongly reduced interaction with CD80, CD86 and ICOSLG. 1 Publication1

Keywords - Diseasei

Diabetes mellitus, Disease mutation, Systemic lupus erythematosus

Organism-specific databases

DisGeNETi1493.
MalaCardsiCTLA4.
MIMi109100. phenotype.
152700. phenotype.
601388. phenotype.
609755. phenotype.
610424. phenotype.
616100. phenotype.
OpenTargetsiENSG00000163599.
Orphaneti555. Celiac disease.
900. Granulomatosis with polyangiitis.
855. Hashimoto struma.
536. Systemic lupus erythematosus.
PharmGKBiPA27006.

Chemistry databases

ChEMBLiCHEMBL2364164.
DrugBankiDB06186. Ipilimumab.
GuidetoPHARMACOLOGYi2743.

Polymorphism and mutation databases

BioMutaiCTLA4.
DMDMi27735177.

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Signal peptidei1 – 35Sequence analysisAdd BLAST35
ChainiPRO_000001473436 – 223Cytotoxic T-lymphocyte protein 4Add BLAST188

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Disulfide bondi58 ↔ 129Combined sources6 Publications
Disulfide bondi85 ↔ 103Combined sources6 Publications
Glycosylationi113N-linked (GlcNAc...) asparagine3 Publications1
Glycosylationi145N-linked (GlcNAc...) asparagine2 Publications1
Disulfide bondi157InterchainCombined sources2 Publications
Modified residuei201Phosphotyrosine; by TXK and JAK23 Publications1

Post-translational modificationi

N-glycosylation is important for dimerization.3 Publications
Phosphorylation at Tyr-201 prevents binding to the AP-2 adapter complex, blocks endocytosis, and leads to retention of CTLA4 on the cell surface.3 Publications

Keywords - PTMi

Disulfide bond, Glycoprotein, Phosphoprotein

Proteomic databases

PaxDbiP16410.
PRIDEiP16410.

PTM databases

iPTMnetiP16410.
PhosphoSitePlusiP16410.

Expressioni

Tissue specificityi

Widely expressed with highest levels in lymphoid tissues. Detected in activated T-cells where expression levels are 30- to 50-fold less than CD28, the stimulatory coreceptor, on the cell surface following activation.3 Publications

Gene expression databases

BgeeiENSG00000163599.
CleanExiHS_CTLA4.
ExpressionAtlasiP16410. baseline and differential.
GenevisibleiP16410. HS.

Interactioni

Subunit structurei

Homodimer; disulfide-linked (PubMed:11279501, PubMed:11279502, Ref. 23, PubMed:21156796, PubMed:28484017). Binds to CD80/B7-1 and CD86/B7.2 (PubMed:11279501, PubMed:11279502, PubMed:28484017). Interacts with ICOSLG (PubMed:28484017).5 Publications

Binary interactionsi

Show more details

Protein-protein interaction databases

BioGridi107875. 109 interactors.
DIPiDIP-35607N.
ELMiP16410.
IntActiP16410. 10 interactors.
MINTiMINT-6631153.
STRINGi9606.ENSP00000303939.

Structurei

Secondary structure

1223
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Beta strandi39 – 41Combined sources3
Beta strandi44 – 47Combined sources4
Beta strandi50 – 52Combined sources3
Beta strandi54 – 60Combined sources7
Beta strandi64 – 66Combined sources3
Beta strandi68 – 77Combined sources10
Beta strandi80 – 90Combined sources11
Beta strandi102 – 108Combined sources7
Beta strandi111 – 116Combined sources6
Helixi121 – 123Combined sources3
Beta strandi125 – 138Combined sources14
Beta strandi140 – 143Combined sources4
Beta strandi147 – 150Combined sources4
Beta strandi156 – 158Combined sources3

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
1AH1NMR-A37-161[»]
1H6EX-ray3.60P197-207[»]
1I85X-ray3.20C/D36-161[»]
1I8LX-ray3.00C/D36-161[»]
2X44X-ray2.60D36-161[»]
3BX7X-ray2.10C38-161[»]
3OSKX-ray1.80A/B36-161[»]
5GGVX-ray2.00Y36-161[»]
5TRUX-ray3.00C/c37-154[»]
ProteinModelPortaliP16410.
SMRiP16410.
ModBaseiSearch...
MobiDBiSearch...

Miscellaneous databases

EvolutionaryTraceiP16410.

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini39 – 140Ig-like V-typeAdd BLAST102

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni46 – 50Homodimerization1 Publication5
Regioni134 – 139Important for interaction with CD80 and CD861 Publication6
Regioni150 – 155Homodimerization2 Publications6

Keywords - Domaini

Immunoglobulin domain, Signal, Transmembrane, Transmembrane helix

Phylogenomic databases

eggNOGiENOG410IJ05. Eukaryota.
ENOG410YUQR. LUCA.
GeneTreeiENSGT00530000063873.
HOGENOMiHOG000112047.
HOVERGENiHBG057978.
InParanoidiP16410.
KOiK06538.
OMAiFSKGMHV.
OrthoDBiEOG091G0IGY.
PhylomeDBiP16410.
TreeFamiTF335679.

Family and domain databases

Gene3Di2.60.40.10. 1 hit.
InterProiView protein in InterPro
IPR008096. CTLA4.
IPR007110. Ig-like_dom.
IPR013783. Ig-like_fold.
IPR003599. Ig_sub.
IPR013106. Ig_V-set.
PfamiView protein in Pfam
PF07686. V-set. 1 hit.
PRINTSiPR01720. CTLANTIGEN4.
SMARTiView protein in SMART
SM00409. IG. 1 hit.
SM00406. IGv. 1 hit.
SUPFAMiSSF48726. SSF48726. 1 hit.

Sequences (5)i

Sequence statusi: Complete.

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

This entry describes 5 isoformsi produced by alternative splicing. AlignAdd to basket

Isoform 1 (identifier: P16410-1) [UniParc]FASTAAdd to basket

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

« Hide

        10         20         30         40         50
MACLGFQRHK AQLNLATRTW PCTLLFFLLF IPVFCKAMHV AQPAVVLASS
60 70 80 90 100
RGIASFVCEY ASPGKATEVR VTVLRQADSQ VTEVCAATYM MGNELTFLDD
110 120 130 140 150
SICTGTSSGN QVNLTIQGLR AMDTGLYICK VELMYPPPYY LGIGNGTQIY
160 170 180 190 200
VIDPEPCPDS DFLLWILAAV SSGLFFYSFL LTAVSLSKML KKRSPLTTGV
210 220
YVKMPPTEPE CEKQFQPYFI PIN
Length:223
Mass (Da):24,656
Last modified:January 10, 2003 - v3
Checksum:i6F9466FB2E139A5A
GO
Isoform 2 (identifier: P16410-2) [UniParc]FASTAAdd to basket
Also known as: ss-CTLA-4

The sequence of this isoform differs from the canonical sequence as follows:
     38-204: Missing.

Show »
Length:56
Mass (Da):6,560
Checksum:i096CBF7AD57AE9B9
GO
Isoform 3 (identifier: P16410-3) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     38-204: Missing.
     205-223: PPTEPECEKQFQPYFIPIN → KEKKPSYNRGLCENAPNRARM

Show »
Length:58
Mass (Da):6,745
Checksum:i5F70948EEDC80A94
GO
Isoform 4 (identifier: P16410-4) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     58-58: C → S
     59-204: Missing.
     205-223: PPTEPECEKQFQPYFIPIN → KEKKPSYNRGLCENAPNRARM

Show »
Length:79
Mass (Da):8,855
Checksum:i60CBF1BC1DA59D8A
GO
Isoform 5 (identifier: P16410-5) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     153-174: DPEPCPDSDFLLWILAAVSSGL → AKEKKPSYNRGLCENAPNRARM
     175-223: Missing.

Show »
Length:174
Mass (Da):19,145
Checksum:i0881BFA757AC3FDB
GO

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti37A → V in ABG85285 (PubMed:18595775).Curated1
Sequence conflicti147T → A in AAA52773 (PubMed:3220103).Curated1

Polymorphismi

Genetic variations in CTLA4 are associated with susceptibility to several autoimmune disorders (PubMed:18595775, PubMed:12724780, PubMed:10189842, PubMed:10924276, PubMed:15138458, PubMed:15657618, PubMed:15688186, PubMed:25329329, PubMed:25213377). They influence responsiveness to hepatitis B virus (HBV) infection [MIMi:610424] (PubMed:15452244).10 Publications

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_01357717T → A Increased risk for Graves disease, insulin-dependent diabetes mellitus, thyroid-associated orbitopathy, systemic lupus erythematosus and susceptibility to HBV infection. 7 PublicationsCorresponds to variant dbSNP:rs231775Ensembl.1
Natural variantiVAR_07268170R → W in ALPS5. 1 PublicationCorresponds to variant dbSNP:rs606231422Ensembl.1

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_04128438 – 204Missing in isoform 2 and isoform 3. 1 PublicationAdd BLAST167
Alternative sequenceiVSP_04128558C → S in isoform 4. 1 Publication1
Alternative sequenceiVSP_04128659 – 204Missing in isoform 4. 1 PublicationAdd BLAST146
Alternative sequenceiVSP_047238153 – 174DPEPC…VSSGL → AKEKKPSYNRGLCENAPNRA RM in isoform 5. 1 PublicationAdd BLAST22
Alternative sequenceiVSP_047239175 – 223Missing in isoform 5. 1 PublicationAdd BLAST49
Alternative sequenceiVSP_041287205 – 223PPTEP…FIPIN → KEKKPSYNRGLCENAPNRAR M in isoform 3 and isoform 4. 1 PublicationAdd BLAST19

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
L15006 mRNA. Translation: AAB59385.1.
M74363 Genomic DNA. Translation: AAA52127.1.
AF411058 Genomic DNA. Translation: AAL40932.1.
AY792514 mRNA. Translation: AAV66331.1.
AY999702 mRNA. Translation: AAY00166.1.
DQ785106 mRNA. Translation: ABG85285.1.
AF414120 mRNA. Translation: AAL07473.1.
DQ357942 Genomic DNA. Translation: ABC67470.1.
AC010138 Genomic DNA. Translation: AAX93176.1.
BC074842 mRNA. Translation: AAH74842.1.
BC074893 mRNA. Translation: AAH74893.1.
AH002733 Genomic DNA. Translation: AAA52773.1.
U90273 mRNA. Translation: AAD00698.1.
AF142144 Genomic DNA. Translation: AAF02499.1.
CCDSiCCDS2362.1. [P16410-1]
CCDS42803.1. [P16410-5]
PIRiS08614.
RefSeqiNP_001032720.1. NM_001037631.2. [P16410-5]
NP_005205.2. NM_005214.4. [P16410-1]
UniGeneiHs.247824.

Genome annotation databases

EnsembliENST00000295854; ENSP00000295854; ENSG00000163599. [P16410-5]
ENST00000302823; ENSP00000303939; ENSG00000163599. [P16410-1]
ENST00000472206; ENSP00000417779; ENSG00000163599. [P16410-4]
GeneIDi1493.
KEGGihsa:1493.
UCSCiuc002vak.3. human. [P16410-1]

Keywords - Coding sequence diversityi

Alternative splicing, Polymorphism

Similar proteinsi

Entry informationi

Entry nameiCTLA4_HUMAN
AccessioniPrimary (citable) accession number: P16410
Secondary accession number(s): A0N1S0
, E9PDH0, O95653, Q0PP65, Q52MC1, Q53TD5, Q5S005, Q8WXJ1, Q96P43, Q9UKN9
Entry historyiIntegrated into UniProtKB/Swiss-Prot: August 1, 1990
Last sequence update: January 10, 2003
Last modified: September 27, 2017
This is version 197 of the entry and version 3 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, Pharmaceutical, Reference proteome

Documents

  1. Human cell differentiation molecules
    CD nomenclature of surface proteins of human leucocytes and list of entries
  2. Human chromosome 2
    Human chromosome 2: entries, gene names and cross-references to MIM
  3. Human entries with polymorphisms or disease mutations
    List of human entries with polymorphisms or disease mutations
  4. Human polymorphisms and disease mutations
    Index of human polymorphisms and disease mutations
  5. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  6. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references