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Protein

T-cell surface glycoprotein CD4

Gene

CD4

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

Functioni

Integral membrane glycoprotein that plays an essential role in the immune response and serves multiple functions in responses against both external and internal offenses. In T-cells, functions primarily as a coreceptor for MHC class II molecule:peptide complex. The antigens presented by class II peptides are derived from extracellular proteins while class I peptides are derived from cytosolic proteins. Interacts simultaneously with the T-cell receptor (TCR) and the MHC class II presented by antigen presenting cells (APCs). In turn, recruits the Src kinase LCK to the vicinity of the TCR-CD3 complex. LCK then initiates different intracellular signaling pathways by phosphorylating various substrates ultimately leading to lymphokine production, motility, adhesion and activation of T-helper cells. In other cells such as macrophages or NK cells, plays a role in differentiation/activation, cytokine expression and cell migration in a TCR/LCK-independent pathway. Participates in the development of T-helper cells in the thymus and triggers the differentiation of monocytes into functional mature macrophages.3 Publications
(Microbial infection) Primary receptor for human immunodeficiency virus-1 (HIV-1) (PubMed:2214026, PubMed:16331979, PubMed:9641677, PubMed:12089508). Down-regulated by HIV-1 Vpu (PubMed:17346169). Acts as a receptor for Human Herpes virus 7/HHV-7 (PubMed:7909607).6 Publications

GO - Molecular functioni

  • coreceptor activity Source: ProtInc
  • enzyme binding Source: UniProtKB
  • extracellular matrix structural constituent Source: UniProtKB
  • immunoglobulin binding Source: Ensembl
  • interleukin-16 binding Source: CAFA
  • interleukin-16 receptor activity Source: CAFA
  • MHC class II protein binding Source: UniProtKB
  • protein homodimerization activity Source: UniProtKB
  • protein kinase binding Source: UniProtKB
  • protein tyrosine kinase binding Source: Ensembl
  • receptor activity Source: ProtInc
  • transmembrane signaling receptor activity Source: ProtInc
  • virus receptor activity Source: UniProtKB-KW
  • zinc ion binding Source: UniProtKB

GO - Biological processi

  • adaptive immune response Source: UniProtKB-KW
  • cell adhesion Source: InterPro
  • cell surface receptor signaling pathway Source: ProtInc
  • cellular response to granulocyte macrophage colony-stimulating factor stimulus Source: CAFA
  • cytokine production Source: Ensembl
  • defense response to Gram-negative bacterium Source: Ensembl
  • entry into host cell Source: Reactome
  • enzyme linked receptor protein signaling pathway Source: ProtInc
  • fusion of virus membrane with host plasma membrane Source: Reactome
  • helper T cell enhancement of adaptive immune response Source: Ensembl
  • immune response Source: UniProtKB
  • induction by virus of host cell-cell fusion Source: UniProtKB
  • interleukin-15-mediated signaling pathway Source: CAFA
  • maintenance of protein location in cell Source: MGI
  • membrane organization Source: Reactome
  • positive regulation of calcium ion transport into cytosol Source: Ensembl
  • positive regulation of calcium-mediated signaling Source: Ensembl
  • positive regulation of ERK1 and ERK2 cascade Source: CAFA
  • positive regulation of I-kappaB kinase/NF-kappaB signaling Source: CAFA
  • positive regulation of interleukin-2 biosynthetic process Source: UniProtKB
  • positive regulation of kinase activity Source: CAFA
  • positive regulation of MAPK cascade Source: CAFA
  • positive regulation of monocyte differentiation Source: CAFA
  • positive regulation of peptidyl-tyrosine phosphorylation Source: Ensembl
  • positive regulation of protein kinase activity Source: UniProtKB
  • positive regulation of protein phosphorylation Source: CAFA
  • positive regulation of T cell proliferation Source: Ensembl
  • positive regulation of transcription, DNA-templated Source: CAFA
  • positive regulation of viral entry into host cell Source: CAFA
  • regulation of calcium ion transport Source: CAFA
  • regulation of defense response to virus by virus Source: Reactome
  • regulation of T cell activation Source: UniProtKB
  • response to estradiol Source: Ensembl
  • response to vitamin D Source: Ensembl
  • signal transduction Source: ProtInc
  • T cell costimulation Source: Reactome
  • T cell differentiation Source: UniProtKB
  • T cell receptor signaling pathway Source: Reactome
  • T cell selection Source: UniProtKB
  • transmembrane receptor protein tyrosine kinase signaling pathway Source: UniProtKB

Keywordsi

Molecular functionHost cell receptor for virus entry, Receptor
Biological processAdaptive immunity, Host-virus interaction, Immunity

Enzyme and pathway databases

ReactomeiR-HSA-1462054. Alpha-defensins.
R-HSA-167590. Nef Mediated CD4 Down-regulation.
R-HSA-173107. Binding and entry of HIV virion.
R-HSA-180534. Vpu mediated degradation of CD4.
R-HSA-202424. Downstream TCR signaling.
R-HSA-202427. Phosphorylation of CD3 and TCR zeta chains.
R-HSA-202430. Translocation of ZAP-70 to Immunological synapse.
R-HSA-202433. Generation of second messenger molecules.
R-HSA-389948. PD-1 signaling.
R-HSA-449836. Other interleukin signaling.
R-HSA-8856825. Cargo recognition for clathrin-mediated endocytosis.
R-HSA-8856828. Clathrin-mediated endocytosis.
SignaLinkiP01730.
SIGNORiP01730.

Names & Taxonomyi

Protein namesi
Recommended name:
T-cell surface glycoprotein CD4
Alternative name(s):
T-cell surface antigen T4/Leu-3
CD_antigen: CD4
Gene namesi
Name:CD4
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 12

Organism-specific databases

EuPathDBiHostDB:ENSG00000010610.9.
HGNCiHGNC:1678. CD4.

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 domaini26 – 396ExtracellularSequence analysisAdd BLAST371
Transmembranei397 – 418HelicalSequence analysisAdd BLAST22
Topological domaini419 – 458CytoplasmicSequence analysisAdd BLAST40

Keywords - Cellular componenti

Cell membrane, Membrane

Pathology & Biotechi

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi432M → T: No effect. 1 Publication1
Mutagenesisi433S → A: About 75% loss of internalization. 1 Publication1
Mutagenesisi433S → A: No effect. 1 Publication1
Mutagenesisi438 – 439LL → AA: Loss of Nef-induced CD4 down-modulation. 1 Publication2
Mutagenesisi440S → L: No effect. 1 Publication1
Mutagenesisi445C → A: Loss of homodimerization; when associated with A-447. 1 Publication1
Mutagenesisi447C → A: Loss of homodimerization; when associated with A-445. 1 Publication1
Mutagenesisi457 – 458Missing : Abolished interaction with SPG21 and induced T-cell activation. 1 Publication2

Organism-specific databases

DisGeNETi920.
MalaCardsiCD4.
MIMi613949. phenotype.
OpenTargetsiENSG00000010610.
PharmGKBiPA26220.

Chemistry databases

ChEMBLiCHEMBL2754.
DrugBankiDB00098. Anti-thymocyte Globulin (Rabbit).

Polymorphism and mutation databases

BioMutaiCD4.
DMDMi116013.

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Signal peptidei1 – 252 PublicationsAdd BLAST25
ChainiPRO_000001462126 – 458T-cell surface glycoprotein CD4Add BLAST433

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Disulfide bondi41 ↔ 109PROSITE-ProRule annotation1 Publication
Disulfide bondi155 ↔ 184PROSITE-ProRule annotation1 Publication
GlycosylationiCAR_000053296N-linked (GlcNAc...) asparagine3 Publications1
GlycosylationiCAR_000054325N-linked (GlcNAc...) asparagine2 Publications1
Disulfide bondi328 ↔ 370PROSITE-ProRule annotation1 Publication
Lipidationi419S-palmitoyl cysteine1 Publication1
Lipidationi422S-palmitoyl cysteine1 Publication1
Modified residuei433Phosphoserine1 Publication1
Modified residuei440Phosphoserine1 Publication1
Modified residuei456Phosphoserine1 Publication1

Post-translational modificationi

Palmitoylation and association with LCK contribute to the enrichment of CD4 in lipid rafts.1 Publication
Phosphorylated by PKC; phosphorylation at Ser-433 plays an important role for CD4 internalization.2 Publications

Keywords - PTMi

Disulfide bond, Glycoprotein, Lipoprotein, Palmitate, Phosphoprotein

Proteomic databases

MaxQBiP01730.
PaxDbiP01730.
PeptideAtlasiP01730.
PRIDEiP01730.

PTM databases

iPTMnetiP01730.
PhosphoSitePlusiP01730.
SwissPalmiP01730.
UniCarbKBiP01730.

Expressioni

Tissue specificityi

Highly expressed in T-helper cells. The presence of CD4 is a hallmark of T-helper cells which are specialized in the activation and growth of cytotoxic T-cells, regulation of B cells, or activation of phagocytes. CD4 is also present in other immune cells such as macrophages, dendritic cells or NK cells.3 Publications

Gene expression databases

BgeeiENSG00000010610.
CleanExiHS_CD4.
ExpressionAtlasiP01730. baseline and differential.
GenevisibleiP01730. HS.

Organism-specific databases

HPAiCAB000011.
CAB068180.
HPA004252.
HPA004472.

Interactioni

Subunit structurei

Forms disulfide-linked homo-dimers at the cell surface. Interacts with LCK (PubMed:16888650). Interacts with PTK2/FAK1. Binds to P4HB/PDI. Interacts with IL16; this interaction induces a CD4-dependent signaling in lymphocytes.5 Publications
(Microbial infection) Interacts with HIV-1 Envelope polyprotein gp160 and protein Vpu (PubMed:2214026, PubMed:16331979, PubMed:9641677).3 Publications
(Microbial infection) Interacts with Human Herpes virus 7 surface proteins.1 Publication

Binary interactionsi

Show more details

GO - Molecular functioni

  • enzyme binding Source: UniProtKB
  • immunoglobulin binding Source: Ensembl
  • interleukin-16 binding Source: CAFA
  • MHC class II protein binding Source: UniProtKB
  • protein homodimerization activity Source: UniProtKB
  • protein kinase binding Source: UniProtKB
  • protein tyrosine kinase binding Source: Ensembl

Protein-protein interaction databases

BioGridi107358. 94 interactors.
DIPiDIP-617N.
ELMiP01730.
IntActiP01730. 19 interactors.
MINTiMINT-1130311.
STRINGi9606.ENSP00000011653.

Chemistry databases

BindingDBiP01730.

Structurei

Secondary structure

1458
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Beta strandi27 – 32Combined sources6
Beta strandi37 – 39Combined sources3
Beta strandi44 – 47Combined sources4
Beta strandi51 – 55Combined sources5
Beta strandi56 – 58Combined sources3
Beta strandi60 – 65Combined sources6
Beta strandi68 – 71Combined sources4
Beta strandi73 – 76Combined sources4
Helixi77 – 79Combined sources3
Helixi84 – 89Combined sources6
Beta strandi94 – 96Combined sources3
Helixi101 – 103Combined sources3
Beta strandi105 – 111Combined sources7
Beta strandi114 – 129Combined sources16
Beta strandi131 – 134Combined sources4
Beta strandi135 – 137Combined sources3
Beta strandi139 – 144Combined sources6
Beta strandi152 – 156Combined sources5
Beta strandi158 – 160Combined sources3
Beta strandi162 – 164Combined sources3
Beta strandi166 – 171Combined sources6
Helixi176 – 178Combined sources3
Beta strandi180 – 188Combined sources9
Beta strandi191 – 200Combined sources10
Helixi398 – 421Combined sources24
Beta strandi426 – 428Combined sources3
Helixi432 – 438Combined sources7
Beta strandi440 – 442Combined sources3

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
1CDHX-ray2.30A26-203[»]
1CDIX-ray2.90A26-203[»]
1CDJX-ray2.50A26-203[»]
1CDUX-ray2.70A26-203[»]
1CDYX-ray2.00A26-203[»]
1G9MX-ray2.20C26-208[»]
1G9NX-ray2.90C26-208[»]
1GC1X-ray2.50C26-206[»]
1JL4X-ray4.30D26-203[»]
1OPNmodel-C26-206[»]
1OPTmodel-C26-206[»]
1OPWmodel-C26-206[»]
1Q68NMR-A421-458[»]
1RZJX-ray2.20C26-208[»]
1RZKX-ray2.90C26-208[»]
1WBRNMR-A428-444[»]
1WIOX-ray3.90A/B26-388[»]
1WIPX-ray4.00A/B26-388[»]
1WIQX-ray5.00A/B26-388[»]
2B4CX-ray3.30C26-206[»]
2JKRX-ray2.98P/Q431-441[»]
2JKTX-ray3.40P/Q435-441[»]
2KLUNMR-A397-458[»]
2NXYX-ray2.00B26-208[»]
2NXZX-ray2.04B26-208[»]
2NY0X-ray2.20B26-208[»]
2NY1X-ray1.99B26-208[»]
2NY2X-ray2.00B26-208[»]
2NY3X-ray2.00B26-208[»]
2NY4X-ray2.00B26-208[»]
2NY5X-ray2.50C26-208[»]
2NY6X-ray2.80B26-208[»]
2QADX-ray3.30B/F26-206[»]
3B71X-ray2.82D/E/F428-450[»]
3CD4X-ray2.20A26-207[»]
3J70electron microscopy-C/O/T26-208[»]
3JCBelectron microscopy-D26-200[»]
3JCCelectron microscopy-D26-200[»]
3JWDX-ray2.61C/D26-208[»]
3JWOX-ray3.51C26-208[»]
3LQAX-ray3.40C26-207[»]
3O2DX-ray2.19A26-207[»]
3S4SX-ray2.40G/H26-203[»]
3S5LX-ray2.10G/H26-203[»]
3T0EX-ray4.00E26-388[»]
4H8WX-ray1.85C26-208[»]
4JM2X-ray3.10F26-208[»]
4P9HX-ray3.00C26-207[»]
4Q6IX-ray3.65C/I/J/K1-208[»]
4R2GX-ray3.28B/F/H/L26-208[»]
4R4HX-ray4.28B26-203[»]
4RQSX-ray4.49B26-208[»]
5A7Xelectron microscopy17.00B/F/J26-206[»]
5A8Helectron microscopy23.00B/H/N26-208[»]
5CAYX-ray3.00B26-208[»]
5THRelectron microscopy8.90G/H/I26-207[»]
5U1Felectron microscopy6.80M26-388[»]
DisProtiDP00123.
ProteinModelPortaliP01730.
SMRiP01730.
ModBaseiSearch...
MobiDBiSearch...

Miscellaneous databases

EvolutionaryTraceiP01730.

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini26 – 125Ig-like V-typeAdd BLAST100
Domaini126 – 203Ig-like C2-type 1Add BLAST78
Domaini204 – 317Ig-like C2-type 2Add BLAST114
Domaini318 – 374Ig-like C2-type 3Add BLAST57

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni427 – 455HIV-1 Vpu-susceptibility domainAdd BLAST29

Keywords - Domaini

Immunoglobulin domain, Repeat, Signal, Transmembrane, Transmembrane helix

Phylogenomic databases

eggNOGiENOG410IK9F. Eukaryota.
ENOG410YWI4. LUCA.
GeneTreeiENSGT00390000001745.
HOGENOMiHOG000008696.
HOVERGENiHBG005281.
InParanoidiP01730.
KOiK06454.
OMAiPEAGMWQ.
OrthoDBiEOG091G0AZL.
PhylomeDBiP01730.
TreeFamiTF335974.

Family and domain databases

Gene3Di2.60.40.10. 3 hits.
InterProiView protein in InterPro
IPR000973. CD4.
IPR015274. CD4-extracel.
IPR007110. Ig-like_dom.
IPR013783. Ig-like_fold.
IPR008424. Ig_C2-set.
IPR003599. Ig_sub.
IPR003598. Ig_sub2.
IPR013106. Ig_V-set.
IPR013151. Immunoglobulin.
IPR021963. Tcell_CD4_Cterm.
PANTHERiPTHR11422:SF3. PTHR11422:SF3. 1 hit.
PfamiView protein in Pfam
PF05790. C2-set. 2 hits.
PF09191. CD4-extracel. 1 hit.
PF00047. ig. 1 hit.
PF12104. Tcell_CD4_C. 1 hit.
PRINTSiPR00692. CD4TCANTIGEN.
SMARTiView protein in SMART
SM00409. IG. 3 hits.
SM00408. IGc2. 2 hits.
SM00406. IGv. 1 hit.
SUPFAMiSSF48726. SSF48726. 4 hits.
PROSITEiView protein in PROSITE
PS50835. IG_LIKE. 1 hit.

Sequencei

Sequence statusi: Complete.

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

P01730-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MNRGVPFRHL LLVLQLALLP AATQGKKVVL GKKGDTVELT CTASQKKSIQ
60 70 80 90 100
FHWKNSNQIK ILGNQGSFLT KGPSKLNDRA DSRRSLWDQG NFPLIIKNLK
110 120 130 140 150
IEDSDTYICE VEDQKEEVQL LVFGLTANSD THLLQGQSLT LTLESPPGSS
160 170 180 190 200
PSVQCRSPRG KNIQGGKTLS VSQLELQDSG TWTCTVLQNQ KKVEFKIDIV
210 220 230 240 250
VLAFQKASSI VYKKEGEQVE FSFPLAFTVE KLTGSGELWW QAERASSSKS
260 270 280 290 300
WITFDLKNKE VSVKRVTQDP KLQMGKKLPL HLTLPQALPQ YAGSGNLTLA
310 320 330 340 350
LEAKTGKLHQ EVNLVVMRAT QLQKNLTCEV WGPTSPKLML SLKLENKEAK
360 370 380 390 400
VSKREKAVWV LNPEAGMWQC LLSDSGQVLL ESNIKVLPTW STPVQPMALI
410 420 430 440 450
VLGGVAGLLL FIGLGIFFCV RCRHRRRQAE RMSQIKRLLS EKKTCQCPHR

FQKTCSPI
Length:458
Mass (Da):51,111
Last modified:November 1, 1988 - v1
Checksum:i20ED893F9E56D236
GO

Polymorphismi

The OKT monoclonal antibodies are widely used for the analysis of human peripheral blood T-lymphocytes. OKT4 reacts with T-helper/inducer lymphocytes. The OKT4 epitope of the CD4 cell-surface protein is polymorphic in white, black, and Japanese populations. The variable phenotypic expression is due a CD4 polymorphism. OKT4 positive individuals carry Arg-265 and OKT4 negative individuals carry Trp-265 [MIMi:613949].2 Publications

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_023459191K → E1 PublicationCorresponds to variant dbSNP:rs28917504Ensembl.1
Natural variantiVAR_023460227F → S1 PublicationCorresponds to variant dbSNP:rs11064419Ensembl.1
Natural variantiVAR_003906265R → W in OKT4-negative populations. 3 PublicationsCorresponds to variant dbSNP:rs28919570Ensembl.1

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
M12807 mRNA. Translation: AAA35572.1.
U47924 Genomic DNA. Translation: AAB51309.1.
M35160 mRNA. Translation: AAA16069.1.
BT019791 mRNA. Translation: AAV38594.1.
BT019811 mRNA. Translation: AAV38614.1.
DQ012936 Genomic DNA. Translation: AAY22175.1.
AK312828 mRNA. Translation: BAG35684.1.
CH471116 Genomic DNA. Translation: EAW88738.1.
CH471116 Genomic DNA. Translation: EAW88739.1.
BC025782 mRNA. Translation: AAH25782.1.
CCDSiCCDS8562.1.
PIRiA90872. RWHUT4.
RefSeqiNP_000607.1. NM_000616.4.
UniGeneiHs.631659.

Genome annotation databases

EnsembliENST00000011653; ENSP00000011653; ENSG00000010610.
GeneIDi920.
KEGGihsa:920.
UCSCiuc001qqv.3. human.

Keywords - Coding sequence diversityi

Polymorphism

Similar proteinsi

Entry informationi

Entry nameiCD4_HUMAN
AccessioniPrimary (citable) accession number: P01730
Secondary accession number(s): B2R737
, D3DUS5, Q4ZGK2, Q5U066, Q9UDE5
Entry historyiIntegrated into UniProtKB/Swiss-Prot: July 21, 1986
Last sequence update: November 1, 1988
Last modified: September 27, 2017
This is version 207 of the entry and version 1 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Miscellaneousi

Keywords - Technical termi

3D-structure, Complete proteome, Direct protein sequencing, Reference proteome

Documents

  1. Human cell differentiation molecules
    CD nomenclature of surface proteins of human leucocytes and list of entries
  2. Human chromosome 12
    Human chromosome 12: 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