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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

GO - Biological processi

  1. B cell receptor signaling pathway Source: UniProtKB
  2. cellular response to DNA damage stimulus Source: UniProtKB
  3. immune response Source: ProtInc
  4. negative regulation of B cell proliferation Source: UniProtKB
  5. negative regulation of immune response Source: Ensembl
  6. negative regulation of regulatory T cell differentiation Source: BHF-UCL
  7. negative regulation of T cell proliferation Source: Ensembl
  8. positive regulation of apoptotic process Source: UniProtKB
  9. T cell costimulation Source: Reactome
Complete GO annotation...

Keywords - Biological processi

Adaptive immunity, Immunity

Enzyme and pathway databases

ReactomeiREACT_19405. CTLA4 inhibitory signaling.

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
ProteomesiUP000005640 Componenti: Chromosome 2

Organism-specific databases

HGNCiHGNC:2505. CTLA4.

Subcellular locationi

  1. Cell membrane 1 Publication; Single-pass type I membrane protein 1 Publication

  2. Note: Exists primarily an intracellular antigen whose surface expression is tightly regulated by restricted trafficking to the cell surface and rapid internalisation;.

Topology

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Topological domaini36 – 161126ExtracellularSequence AnalysisAdd
BLAST
Transmembranei162 – 18221HelicalSequence AnalysisAdd
BLAST
Topological domaini183 – 22341CytoplasmicSequence AnalysisAdd
BLAST

GO - Cellular componenti

  1. clathrin-coated endocytic vesicle Source: BHF-UCL
  2. external side of plasma membrane Source: BHF-UCL
  3. Golgi apparatus Source: BHF-UCL
  4. integral component of plasma membrane Source: ProtInc
  5. perinuclear region of cytoplasm Source: BHF-UCL
  6. plasma membrane Source: Reactome
Complete GO annotation...

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.

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)LengthDescriptionGraphical viewFeature identifierActions
Natural varianti70 – 701R → W in ALPS5. 1 Publication
VAR_072681

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.

Keywords - Diseasei

Diabetes mellitus, Disease mutation, Systemic lupus erythematosus

Organism-specific databases

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

Chemistry

DrugBankiDB06186. Ipilimumab.

Polymorphism and mutation databases

BioMutaiCTLA4.
DMDMi27735177.

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Signal peptidei1 – 3535Sequence AnalysisAdd
BLAST
Chaini36 – 223188Cytotoxic T-lymphocyte protein 4PRO_0000014734Add
BLAST

Amino acid modifications

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Disulfide bondi58 ↔ 129
Disulfide bondi85 ↔ 103
Glycosylationi113 – 1131N-linked (GlcNAc...)3 Publications
Glycosylationi145 – 1451N-linked (GlcNAc...)2 Publications
Disulfide bondi157 – 157Interchain
Modified residuei201 – 2011Phosphotyrosine; by TXK and JAK23 Publications

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

PhosphoSiteiP16410.

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

BgeeiP16410.
CleanExiHS_CTLA4.
ExpressionAtlasiP16410. baseline and differential.
GenevestigatoriP16410.

Interactioni

Subunit structurei

Homodimer; disulfide-linked. Binds to CD80/B7-1 and CD86/B7.2.3 Publications

Binary interactionsi

WithEntry#Exp.IntActNotes
CD80P336813EBI-1030991,EBI-1031024
CD86P420813EBI-1030991,EBI-1030956
PIK3R1P279863EBI-1030991,EBI-79464

Protein-protein interaction databases

BioGridi107875. 11 interactions.
IntActiP16410. 6 interactions.
MINTiMINT-6631153.
STRINGi9606.ENSP00000303939.

Structurei

Secondary structure

1
223
Legend: HelixTurnBeta strand
Show more details
Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Beta strandi44 – 474Combined sources
Beta strandi50 – 523Combined sources
Beta strandi54 – 607Combined sources
Beta strandi64 – 663Combined sources
Beta strandi68 – 7710Combined sources
Beta strandi80 – 9011Combined sources
Beta strandi102 – 1087Combined sources
Beta strandi111 – 1166Combined sources
Helixi121 – 1233Combined sources
Beta strandi125 – 13814Combined sources
Beta strandi140 – 1434Combined sources
Beta strandi147 – 1504Combined sources
Beta strandi156 – 1583Combined sources

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
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[»]
ProteinModelPortaliP16410.
SMRiP16410. Positions 38-160.
ModBaseiSearch...
MobiDBiSearch...

Miscellaneous databases

EvolutionaryTraceiP16410.

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Domaini39 – 140102Ig-like V-typeAdd
BLAST

Region

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Regioni46 – 505Homodimerization
Regioni150 – 1556Homodimerization

Sequence similaritiesi

Keywords - Domaini

Immunoglobulin domain, Signal, Transmembrane, Transmembrane helix

Phylogenomic databases

eggNOGiNOG42442.
GeneTreeiENSGT00530000063873.
HOGENOMiHOG000112047.
HOVERGENiHBG057978.
InParanoidiP16410.
KOiK06538.
OMAiFSKGMHV.
OrthoDBiEOG70GMGW.
PhylomeDBiP16410.
TreeFamiTF335679.

Family and domain databases

Gene3Di2.60.40.10. 1 hit.
InterProiIPR008096. CTLA4.
IPR013783. Ig-like_fold.
IPR013106. Ig_V-set.
[Graphical view]
PfamiPF07686. V-set. 1 hit.
[Graphical view]
PRINTSiPR01720. CTLANTIGEN4.
SMARTiSM00406. IGv. 1 hit.
[Graphical view]

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)LengthDescriptionGraphical viewFeature identifierActions
Sequence conflicti37 – 371A → V in ABG85285 (PubMed:18595775).Curated
Sequence conflicti147 – 1471T → A in AAA52773 (PubMed:3220103).Curated

Polymorphismi

Genetic variations in CTLA4 are associated with susceptibility to several autoimmune disorders. They influence responsiveness to hepatitis B virus (HBV) infection [MIMi:610424].

Natural variant

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Natural varianti17 – 171T → A Increased risk for Graves disease, insulin-dependent diabetes mellitus, thyroid-associated orbitopathy, systemic lupus erythematosus and susceptibility to HBV infection. 7 Publications
Corresponds to variant rs231775 [ dbSNP | Ensembl ].
VAR_013577
Natural varianti70 – 701R → W in ALPS5. 1 Publication
VAR_072681

Alternative sequence

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Alternative sequencei38 – 204167Missing in isoform 2 and isoform 3. 1 PublicationVSP_041284Add
BLAST
Alternative sequencei58 – 581C → S in isoform 4. 1 PublicationVSP_041285
Alternative sequencei59 – 204146Missing in isoform 4. 1 PublicationVSP_041286Add
BLAST
Alternative sequencei153 – 17422DPEPC…VSSGL → AKEKKPSYNRGLCENAPNRA RM in isoform 5. 1 PublicationVSP_047238Add
BLAST
Alternative sequencei175 – 22349Missing in isoform 5. 1 PublicationVSP_047239Add
BLAST
Alternative sequencei205 – 22319PPTEP…FIPIN → KEKKPSYNRGLCENAPNRAR M in isoform 3 and isoform 4. 1 PublicationVSP_041287Add
BLAST

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.2. human. [P16410-1]
uc010fty.2. human. [P16410-4]

Polymorphism and mutation databases

BioMutaiCTLA4.

Keywords - Coding sequence diversityi

Alternative splicing, Polymorphism

Cross-referencesi

Web resourcesi

Wikipedia

CLTA-4 entry

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.

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
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[»]
ProteinModelPortaliP16410.
SMRiP16410. Positions 38-160.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi107875. 11 interactions.
IntActiP16410. 6 interactions.
MINTiMINT-6631153.
STRINGi9606.ENSP00000303939.

Chemistry

ChEMBLiCHEMBL2364164.
DrugBankiDB06186. Ipilimumab.
GuidetoPHARMACOLOGYi2743.

PTM databases

PhosphoSiteiP16410.

Polymorphism and mutation databases

BioMutaiCTLA4.
DMDMi27735177.

Proteomic databases

PaxDbiP16410.
PRIDEiP16410.

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENST00000295854; ENSP00000295854; ENSG00000163599. [P16410-5]
ENST00000302823; ENSP00000303939; ENSG00000163599. [P16410-1]
ENST00000472206; ENSP00000417779; ENSG00000163599. [P16410-4]
GeneIDi1493.
KEGGihsa:1493.
UCSCiuc002vak.2. human. [P16410-1]
uc010fty.2. human. [P16410-4]

Organism-specific databases

CTDi1493.
GeneCardsiGC02P204696.
HGNCiHGNC:2505. CTLA4.
MIMi109100. phenotype.
123890. gene.
152700. phenotype.
601388. phenotype.
609755. phenotype.
610424. phenotype.
616100. phenotype.
neXtProtiNX_P16410.
Orphaneti555. Celiac disease.
900. Granulomatosis with polyangiitis.
855. Hashimoto struma.
536. Systemic lupus erythematosus.
PharmGKBiPA27006.
GenAtlasiSearch...

Phylogenomic databases

eggNOGiNOG42442.
GeneTreeiENSGT00530000063873.
HOGENOMiHOG000112047.
HOVERGENiHBG057978.
InParanoidiP16410.
KOiK06538.
OMAiFSKGMHV.
OrthoDBiEOG70GMGW.
PhylomeDBiP16410.
TreeFamiTF335679.

Enzyme and pathway databases

ReactomeiREACT_19405. CTLA4 inhibitory signaling.

Miscellaneous databases

EvolutionaryTraceiP16410.
GeneWikiiCTLA-4.
GenomeRNAii1493.
NextBioi13603519.
PROiP16410.
SOURCEiSearch...

Gene expression databases

BgeeiP16410.
CleanExiHS_CTLA4.
ExpressionAtlasiP16410. baseline and differential.
GenevestigatoriP16410.

Family and domain databases

Gene3Di2.60.40.10. 1 hit.
InterProiIPR008096. CTLA4.
IPR013783. Ig-like_fold.
IPR013106. Ig_V-set.
[Graphical view]
PfamiPF07686. V-set. 1 hit.
[Graphical view]
PRINTSiPR01720. CTLANTIGEN4.
SMARTiSM00406. IGv. 1 hit.
[Graphical view]
ProtoNetiSearch...

Publicationsi

« Hide 'large scale' publications
  1. "CTLA-4 and CD28 activated lymphocyte molecules are closely related in both mouse and human as to sequence, message expression, gene structure, and chromosomal location."
    Harper K., Balzano C., Rouvier E., Mattei M.-G., Luciani M.-F., Golstein P.
    J. Immunol. 147:1037-1044(1991) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA] (ISOFORM 1), TISSUE SPECIFICITY, ALTERNATIVE SPLICING, VARIANT ALA-17.
  2. "Assembly and annotation of human chromosome 2q33 sequence containing the CD28, CTLA4, and ICOS gene cluster: analysis by computational, comparative, and microarray approaches."
    Ling V., Wu P.W., Finnerty H.F., Agostino M.J., Graham J.R., Chen S., Jussiff J.M., Fisk G.J., Miller C.P., Collins M.
    Genomics 78:155-168(2001) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
  3. "Identification of CTLA-4 isoforms produced by alternative splicing and their association with myasthenia gravis."
    Gu M., Kakoulidou M., Giscombe R., Pirskanen R., Lefvert A.K., Klareskog L., Wang X.
    Clin. Immunol. 128:374-381(2008) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 2; 3 AND 4), VARIANT ALA-17, ALTERNATIVE SPLICING.
  4. "Full length sequence of hCTLA4 cDNA."
    Wu P.W., Ling V.
    Submitted (AUG-2001) to the EMBL/GenBank/DDBJ databases
    Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
  5. NIEHS SNPs program
    Submitted (JAN-2006) to the EMBL/GenBank/DDBJ databases
    Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
  6. "Generation and annotation of the DNA sequences of human chromosomes 2 and 4."
    Hillier L.W., Graves T.A., Fulton R.S., Fulton L.A., Pepin K.H., Minx P., Wagner-McPherson C., Layman D., Wylie K., Sekhon M., Becker M.C., Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E., Kremitzki C., Oddy L., Du H.
    , Sun H., Bradshaw-Cordum H., Ali J., Carter J., Cordes M., Harris A., Isak A., van Brunt A., Nguyen C., Du F., Courtney L., Kalicki J., Ozersky P., Abbott S., Armstrong J., Belter E.A., Caruso L., Cedroni M., Cotton M., Davidson T., Desai A., Elliott G., Erb T., Fronick C., Gaige T., Haakenson W., Haglund K., Holmes A., Harkins R., Kim K., Kruchowski S.S., Strong C.M., Grewal N., Goyea E., Hou S., Levy A., Martinka S., Mead K., McLellan M.D., Meyer R., Randall-Maher J., Tomlinson C., Dauphin-Kohlberg S., Kozlowicz-Reilly A., Shah N., Swearengen-Shahid S., Snider J., Strong J.T., Thompson J., Yoakum M., Leonard S., Pearman C., Trani L., Radionenko M., Waligorski J.E., Wang C., Rock S.M., Tin-Wollam A.-M., Maupin R., Latreille P., Wendl M.C., Yang S.-P., Pohl C., Wallis J.W., Spieth J., Bieri T.A., Berkowicz N., Nelson J.O., Osborne J., Ding L., Meyer R., Sabo A., Shotland Y., Sinha P., Wohldmann P.E., Cook L.L., Hickenbotham M.T., Eldred J., Williams D., Jones T.A., She X., Ciccarelli F.D., Izaurralde E., Taylor J., Schmutz J., Myers R.M., Cox D.R., Huang X., McPherson J.D., Mardis E.R., Clifton S.W., Warren W.C., Chinwalla A.T., Eddy S.R., Marra M.A., Ovcharenko I., Furey T.S., Miller W., Eichler E.E., Bork P., Suyama M., Torrents D., Waterston R.H., Wilson R.K.
    Nature 434:724-731(2005) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE 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] (ISOFORM 1).
    Tissue: Lung.
  8. "Human Ig superfamily CTLA-4 gene: chromosomal localization and identity of protein sequence between murine and human CTLA-4 cytoplasmic domains."
    Dariavach P., Mattei M.-G., Golstein P., Lefranc M.-P.
    Eur. J. Immunol. 18:1901-1905(1988) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 38-223.
    Tissue: Lymphocyte.
  9. Oaks M.K.
    Submitted (FEB-1997) to the EMBL/GenBank/DDBJ databases
    Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 38-223 (ISOFORM 5).
    Tissue: Lymph node.
  10. "Complete sequence determination of the mouse and human CTLA4 gene loci: cross-species DNA sequence similarity beyond exon borders."
    Ling V., Wu P.W., Finnerty H.F., Sharpe A.H., Gray G.S., Collins M.
    Genomics 60:341-355(1999) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 140-223, TISSUE SPECIFICITY.
  11. "CTLA-4 is a second receptor for the B cell activation antigen B7."
    Linsley P.S., Brady W., Urnes M., Griosmaire L.S., Damle N.K., Ledbetter J.A.
    J. Exp. Med. 174:561-569(1991) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION.
  12. "Tyrosine phosphorylation controls internalization of CTLA-4 by regulating its interaction with clathrin-associated adaptor complex AP-2."
    Shiratori T., Miyatake S., Ohno H., Nakaseko C., Isono K., Bonifacino J.S., Saito T.
    Immunity 6:583-589(1997) [PubMed] [Europe PMC] [Abstract]
    Cited for: PHOSPHORYLATION AT TYR-201.
  13. "Resting lymphocyte kinase (Rlk/Txk) phosphorylates the YVKM motif and regulates PI 3-kinase binding to T-cell antigen CTLA-4."
    Schneider H., Schwartzberg P.L., Rudd C.E.
    Biochem. Biophys. Res. Commun. 252:14-19(1998) [PubMed] [Europe PMC] [Abstract]
    Cited for: PHOSPHORYLATION AT TYR-201.
  14. "Janus kinase 2 is associated with a box 1-like motif and phosphorylates a critical tyrosine residue in the cytoplasmic region of cytotoxic T lymphocyte associated molecule-4."
    Chikuma S., Murakami M., Tanaka K., Uede T.
    J. Cell. Biochem. 78:241-250(2000) [PubMed] [Europe PMC] [Abstract]
    Cited for: PHOSPHORYLATION AT TYR-201 BY JAK2.
  15. "Association of the T-cell regulatory gene CTLA4 with susceptibility to autoimmune disease."
    Ueda H., Howson J.M., Esposito L., Heward J., Snook H., Chamberlain G., Rainbow D.B., Hunter K.M., Smith A.N., Di Genova G., Herr M.H., Dahlman I., Payne F., Smyth D., Lowe C., Twells R.C., Howlett S., Healy B.
    , Nutland S., Rance H.E., Everett V., Smink L.J., Lam A.C., Cordell H.J., Walker N.M., Bordin C., Hulme J., Motzo C., Cucca F., Hess J.F., Metzker M.L., Rogers J., Gregory S., Allahabadia A., Nithiyananthan R., Tuomilehto-Wolf E., Tuomilehto J., Bingley P., Gillespie K.M., Undlien D.E., Ronningen K.S., Guja C., Ionescu-Tirgoviste C., Savage D.A., Maxwell A.P., Carson D.J., Patterson C.C., Franklyn J.A., Clayton D.G., Peterson L.B., Wicker L.S., Todd J.A., Gough S.C.
    Nature 423:506-511(2003) [PubMed] [Europe PMC] [Abstract]
    Cited for: POLYMORPHISM.
  16. "Hierarchical regulation of CTLA-4 dimer-based lattice formation and its biological relevance for T cell inactivation."
    Darlington P.J., Kirchhof M.G., Criado G., Sondhi J., Madrenas J.
    J. Immunol. 175:996-1004(2005) [PubMed] [Europe PMC] [Abstract]
    Cited for: GLYCOSYLATION AT ASN-113 AND ASN-145.
  17. Cited for: FUNCTION, TISSUE SPECIFICITY.
  18. "CTLA-4 trafficking and surface expression."
    Valk E., Rudd C.E., Schneider H.
    Trends Immunol. 29:272-279(2008) [PubMed] [Europe PMC] [Abstract]
    Cited for: SUBCELLULAR LOCATION.
  19. "The clinical utility of inhibiting CD28-mediated costimulation."
    Linsley P.S., Nadler S.G.
    Immunol. Rev. 229:307-321(2009) [PubMed] [Europe PMC] [Abstract]
    Cited for: PHARMACEUTICAL.
  20. "Solution structure of human CTLA-4 and delineation of a CD80/CD86 binding site conserved in CD28."
    Metzler W.J., Bajorath J., Fenderson W., Shaw S.Y., Constantine K.L., Naemura J., Leytze G., Peach R.J., Lavoie T.B., Mueller L., Linsley P.S.
    Nat. Struct. Biol. 4:527-531(1997) [PubMed] [Europe PMC] [Abstract]
    Cited for: STRUCTURE BY NMR OF 37-165.
  21. "Structural basis for co-stimulation by the human CTLA-4/B7-2 complex."
    Schwartz J.C., Zhang X., Fedorov A.A., Nathenson S.G., Almo S.C.
    Nature 410:604-608(2001) [PubMed] [Europe PMC] [Abstract]
    Cited for: X-RAY CRYSTALLOGRAPHY (3.2 ANGSTROMS) OF 36-161 IN COMPLEX WITH CD86, SUBUNIT, DISULFIDE BONDS.
  22. "Crystal structure of the B7-1/CTLA-4 complex that inhibits human immune responses."
    Stamper C.C., Zhang Y., Tobin J.F., Erbe D.V., Ikemizu S., Davis S.J., Stahl M.L., Seehra J., Somers W.S., Mosyak L.
    Nature 410:608-611(2001) [PubMed] [Europe PMC] [Abstract]
    Cited for: X-RAY CRYSTALLOGRAPHY (3.0 ANGSTROMS) OF 36-161 IN COMPLEX WITH CD80, SUBUNIT, DISULFIDE BONDS, GLYCOSYLATION AT ASN-113 AND ASN-145.
  23. "Rigid-body ligand recognition drives cytotoxic T-lymphocyte antigen 4 (CTLA-4) receptor triggering."
    Yu C., Sonnen A.F., George R., Dessailly B.H., Stagg L.J., Evans E.J., Orengo C.A., Stuart D.I., Ladbury J.E., Ikemizu S., Gilbert R.J., Davis S.J.
    J. Biol. Chem. 286:6685-6696(2011) [PubMed] [Europe PMC] [Abstract]
    Cited for: X-RAY CRYSTALLOGRAPHY (1.8 ANGSTROMS) OF 36-161, GLYCOSYLATION AT ASN-113, SUBUNIT, DISULFIDE BONDS.
  24. Cited for: VARIANT ALA-17, INVOLVEMENT IN IDDM12.
  25. "CTLA-4 gene polymorphism is associated with predisposition to coeliac disease."
    Djilali-Saiah I., Schmitz J., Harfouch-Hammoud E., Mougenot J.-F., Bach J.-F., Caillat-Zucman S.
    Gut 43:187-189(1998) [PubMed] [Europe PMC] [Abstract]
    Cited for: POLYMORPHISM, INVOLVEMENT IN CELIAC3.
  26. "Cytotoxic T lymphocyte antigen-4 (CTLA-4) gene polymorphism confers susceptibility to thyroid associated orbitopathy."
    Vaidya B., Imrie H., Perros P., Dickinson J., McCarthy M.I., Kendall-Taylor P., Pearce S.H.S.
    Lancet 354:743-744(1999) [PubMed] [Europe PMC] [Abstract]
    Cited for: VARIANT ALA-17, INVOLVEMENT IN THYROID ASSOCIATED ORBITOPATHY.
  27. Cited for: VARIANT ALA-17, INVOLVEMENT IN GRAVES DISEASE.
  28. "Familial primary pulmonary hypertension (gene PPH1) is caused by mutations in the bone morphogenetic protein receptor-II gene."
    Deng Z., Morse J.H., Slager S.L., Cuervo N., Moore K.J., Venetos G., Kalachikov S., Cayanis E., Fischer S.G., Barst R.J., Hodge S.E., Knowles J.A.
    Am. J. Hum. Genet. 67:737-744(2000) [PubMed] [Europe PMC] [Abstract]
    Cited for: VARIANT ALA-17.
  29. Cited for: INVOLVEMENT IN SYSTEMIC LUPUS ERYTHEMATOSUS.
  30. "Cytotoxic T-lymphocyte antigen 4 gene and recovery from hepatitis B virus infection."
    Thio C.L., Mosbruger T.L., Kaslow R.A., Karp C.L., Strathdee S.A., Vlahov D., O'Brien S.J., Astemborski J., Thomas D.L.
    J. Virol. 78:11258-11262(2004) [PubMed] [Europe PMC] [Abstract]
    Cited for: INVOLVEMENT IN SUSCEPTIBILITY TO HBV INFECTION, VARIANT ALA-17.
  31. Cited for: INVOLVEMENT IN CELIAC3.
  32. "CTLA-4 polymorphisms and systemic lupus erythematosus (SLE): a meta-analysis."
    Lee Y.H., Harley J.B., Nath S.K.
    Hum. Genet. 116:361-367(2005) [PubMed] [Europe PMC] [Abstract]
    Cited for: INVOLVEMENT IN SYSTEMIC LUPUS ERYTHEMATOSUS.
  33. Cited for: INVOLVEMENT IN ALPS5, VARIANT ALPS5 TRP-70.
  34. Cited for: INVOLVEMENT IN ALPS5.

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 historyi
Integrated into UniProtKB/Swiss-Prot: August 1, 1990
Last sequence update: January 10, 2003
Last modified: April 29, 2015
This is version 174 of the entry and version 3 of the sequence. [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
  7. SIMILARITY comments
    Index of protein domains and families

External Data

Dasty 3

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into Uniref entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.