Reviewed, UniProtKB/Swiss-Prot P01730 (CD4_HUMAN)

Names and origin

Protein names

Recommended name:
    T-cell surface glycoprotein CD4
Alternative name(s):
    T-cell surface antigen T4/Leu-3
    CD_antigen=CD4

Gene names

Name:

CD4

Organism

Homo sapiens (Human)

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

Protein attributes

Sequence length	458 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	Accessory protein for MHC class-II antigen/T-cell receptor interaction. May regulate T-cell activation. Induces the aggregation of lipid rafts.
Subunit structure	Associates with LCK. Binds to HIV-1 gp120 and to P4HB/PDI and upon HIV-1 binding to the cell membrane, is part of P4HB/PDI-CD4-CXCR4-gp120 complex. Interacts with HIV-1 Envelope polyprotein gp160 and protein Vpu.
Subcellular location	Cell membrane; Single-pass type I membrane protein. Note= Localizes to lipid rafts. Removed from plasma membrane by HIV-1 Nef protein that increases clathrin-dependent endocytosis of this antigen to target it to lysosomal degradation. Cell surface expression is also down-modulated by HIV-1 Envelope polyprotein gp160 that interacts with, and sequesters CD4 in the endoplasmic reticulum.
Post-translational modification	Palmitoylation and association with LCK contribute to the enrichment of CD4 in lipid rafts.
Miscellaneous	Primary receptor for HIV-1.
Sequence similarities	Contains 3 Ig-like C2-type (immunoglobulin-like) domains. Contains 1 Ig-like V-type (immunoglobulin-like) domain.

Ontologies

Keywords
Biological process	Host-virus interaction Immune response
Cellular component	Cell membrane Membrane
Coding sequence diversity	Polymorphism
Domain	Immunoglobulin domain Repeat Signal Transmembrane
PTM	Glycoprotein Lipoprotein Palmitate
Technical term	3D-structure Direct protein sequencing
Gene Ontology (GO)
Biological process	T cell selection Inferred from direct assay. Source: UniProtKB conjugation with cellular fusion Inferred from direct assay. Source: UniProtKB immune response Non-traceable author statement. Source: UniProtKB initiation of viral infection Inferred from Experiment. Source: Reactome positive regulation of interleukin-2 biosynthetic process Non-traceable author statement. Source: UniProtKB positive regulation of protein kinase activity Inferred from direct assay. Source: UniProtKB regulation of T cell activation Inferred from direct assay. Source: UniProtKB transmembrane receptor protein tyrosine kinase signaling pathway Non-traceable author statement. Source: UniProtKB
Cellular component	T cell receptor complex Non-traceable author statement. Source: UniProtKB early endosome Inferred from Experiment. Source: Reactome endoplasmic reticulum membrane Inferred from Experiment. Source: Reactome
Molecular function	MHC class II protein binding Non-traceable author statement. Source: UniProtKB coreceptor activity Non-traceable author statement. Source: UniProtKB extracellular matrix structural constituent Non-traceable author statement. Source: UniProtKB glycoprotein binding Inferred from physical interaction. Source: UniProtKB protein homodimerization activity Inferred from direct assay. Source: UniProtKB protein kinase binding Inferred from physical interaction. Source: UniProtKB transmembrane receptor activity Traceable author statement. Source: ProtInc zinc ion binding Inferred from direct assay. Source: UniProtKB
Complete GO annotation...

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Molecule processing

Signal peptide

1 – 25

25

Chain

26 – 458

433

T-cell surface glycoprotein CD4

Regions

Topological domain

26 – 396

371

Extracellular Potential

Transmembrane

397 – 418

22

Potential

Topological domain

419 – 458

40

Cytoplasmic Potential

Domain

26 – 125

100

Ig-like V-type

Domain

126 – 203

78

Ig-like C2-type 1

Domain

204 – 317

114

Ig-like C2-type 2

Domain

318 – 374

57

Ig-like C2-type 3

Region

427 – 455

29

HIV-1 Vpu-susceptibility domain

Amino acid modifications

Lipidation

419

1

S-palmitoyl cysteine

Lipidation

422

1

S-palmitoyl cysteine

Glycosylation

296

1

N-linked (GlcNAc...)

Glycosylation

325

1

N-linked (GlcNAc...)

Disulfide bond

41 ↔ 109

Disulfide bond

155 ↔ 184

Disulfide bond

328 ↔ 370

Natural variations

Natural variant

191

1

K → E: dbSNP rs28917504.

Natural variant

227

1

F → S: dbSNP rs11064419.

Natural variant

265

1

R → W in OKT4-negative populations. dbSNP rs28919570.

Experimental info

Mutagenesis

432

1

M → T: No effect

Mutagenesis

433

1

S → A: No effect

Mutagenesis

438 – 439

2

LL → AA: Loss of Nef-induced CD4 down-modulation

Mutagenesis

440

1

S → L: No effect

Mutagenesis

457 – 458

2

Missing: Abolished interaction with SPG21 and induced T-cell activation

Secondary structure

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458

Helix Strand Turn

Details...

Beta strand

27 – 32

6

Beta strand

37 – 39

3

Beta strand

45 – 48

4

Beta strand

50 – 55

6

Beta strand

60 – 63

4

Turn

75 – 79

5

Helix

87 – 89

3

Beta strand

94 – 96

3

Helix

101 – 103

3

Beta strand

105 – 111

7

Beta strand

114 – 129

16

Beta strand

131 – 134

4

Beta strand

141 – 144

4

Beta strand

152 – 156

5

Beta strand

162 – 168

7

Beta strand

171 – 173

3

Beta strand

182 – 187

6

Beta strand

192 – 197

6

Beta strand

200 – 202

3

Beta strand

209 – 214

6

Beta strand

219 – 222

4

Beta strand

234 – 244

11

Beta strand

251 – 256

6

Beta strand

261 – 267

7

Beta strand

276 – 279

4

Beta strand

281 – 287

7

Helix

289 – 291

3

Beta strand

293 – 299

7

Turn

302 – 305

4

Beta strand

308 – 319

12

Beta strand

323 – 333

11

Beta strand

340 – 343

4

Beta strand

345 – 348

4

Beta strand

350 – 362

13

Beta strand

365 – 372

8

Beta strand

374 – 377

4

Beta strand

380 – 386

7

Helix

432 – 438

7

Sequences

	Sequence		Length	Mass (Da)
	P01730-1 [UniParc]. Last modified November 1, 1988. Version 1. Checksum: 20ED893F9E56D236	FASTA	458	51,111
	10 20 30 40 50 60 MNRGVPFRHL LLVLQLALLP AATQGKKVVL GKKGDTVELT CTASQKKSIQ FHWKNSNQIK 70 80 90 100 110 120 ILGNQGSFLT KGPSKLNDRA DSRRSLWDQG NFPLIIKNLK IEDSDTYICE VEDQKEEVQL 130 140 150 160 170 180 LVFGLTANSD THLLQGQSLT LTLESPPGSS PSVQCRSPRG KNIQGGKTLS VSQLELQDSG 190 200 210 220 230 240 TWTCTVLQNQ KKVEFKIDIV VLAFQKASSI VYKKEGEQVE FSFPLAFTVE KLTGSGELWW 250 260 270 280 290 300 QAERASSSKS WITFDLKNKE VSVKRVTQDP KLQMGKKLPL HLTLPQALPQ YAGSGNLTLA 310 320 330 340 350 360 LEAKTGKLHQ EVNLVVMRAT QLQKNLTCEV WGPTSPKLML SLKLENKEAK VSKREKAVWV 370 380 390 400 410 420 LNPEAGMWQC LLSDSGQVLL ESNIKVLPTW STPVQPMALI VLGGVAGLLL FIGLGIFFCV 430 440 450 RCRHRRRQAE RMSQIKRLLS EKKTCQCPHR FQKTCSPI

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"The isolation and nucleotide sequence of a cDNA encoding the T cell surface protein T4: a new member of the immunoglobulin gene family." Maddon P.J., Littman D.R., Godfrey M., Maddon D.E., Chess L., Axel R. Cell 42:93-104(1985) [PubMed: 2990730] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[2]	"Corrected CD4 sequence." Littman D.R., Maddon P.J., Axel R. Cell 55:541-541(1988) [PubMed: 3263213] [Abstract] Cited for: SEQUENCE REVISION TO 26.
[3]	"A gene-rich cluster between the CD4 and triosephosphate isomerase genes at human chromosome 12p13." Ansari-Lari M.A., Muzny D.M., Lu J., Lu F., Lilley C.E., Spanos S., Malley T., Gibbs R.A. Genome Res. 6:314-326(1996) [PubMed: 8723724] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[4]	"Large-scale sequencing in human chromosome 12p13: experimental and computational gene structure determination." Ansari-Lari M.A., Shen Y., Muzny D.M., Lee W., Gibbs R.A. Genome Res. 7:268-280(1997) [PubMed: 9074930] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA]. Tissue: Brain.
[5]	"Humans with OKT4-epitope deficiency have a single nucleotide base change in the CD4 gene, resulting in substitution of TRP240 for ARG240." Hodge T.W., Sasso D.R., McDougal J.S. Hum. Immunol. 30:99-104(1991) [PubMed: 1708753] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], VARIANT TRP-265.
[6]	"NIEHS-SNPs, environmental genome project, NIEHS ES15478, Department of Genome Sciences, Seattle, WA (URL: http://egp.gs.washington.edu)." Livingston R.J., Rieder M.J., Shaffer T., Bertucci C., Baier C.N., Rajkumar N., Willa H.T., Daniels M., Downing T.K., Stanaway I.B., Nguyen C.P., Gildersleeve H., Cassidy C.M., Johnson E.J., Swanson J.E., McFarland I., Yool B., Park C., Nickerson D.A. Submitted (APR-2005) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA], VARIANTS GLU-191; SER-227 AND TRP-265.
[7]	"Cloning of human full-length CDSs in BD Creator(TM) system donor vector." Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S., Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y., Phelan M., Farmer A. Submitted (MAY-2003) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
[8]	"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: 15489334] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Tissue: Pancreas.
[9]	"Cloning and sequences of primate CD4 molecules: diversity of the cellular receptor for simian immunodeficiency virus/human immunodeficiency virus." Fomsgaard A., Hirsch V.M., Johnson P.R. Eur. J. Immunol. 22:2973-2981(1992) [PubMed: 1425921] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 28-424. Tissue: Blood.
[10]	"Protein and carbohydrate structural analysis of a recombinant soluble CD4 receptor by mass spectrometry." Carr S.A., Hemling M.E., Folena-Wasserman G., Sweet R.W., Anumula K., Barr J.R., Huddleston M.J., Taylor P. J. Biol. Chem. 264:21286-21295(1989) [PubMed: 2592374] [Abstract] Cited for: PROTEIN SEQUENCE OF 26-394, DISULFIDE BOND.
[11]	"Signal peptide prediction based on analysis of experimentally verified cleavage sites." Zhang Z., Henzel W.J. Protein Sci. 13:2819-2824(2004) [PubMed: 15340161] [Abstract] Cited for: PROTEIN SEQUENCE OF 26-40.
[12]	"CD4 is retained in the endoplasmic reticulum by the human immunodeficiency virus type 1 glycoprotein precursor." Crise B., Buonocore L., Rose J.K. J. Virol. 64:5585-5593(1990) [PubMed: 2214026] [Abstract] Cited for: INTERACTION WITH HIV-1 ENVELOPE POLYPROTEIN GP160.
[13]	"Identification of palmitoylation sites on CD4, the human immunodeficiency virus receptor." Crise B., Rose J.K. J. Biol. Chem. 267:13593-13597(1992) [PubMed: 1618861] [Abstract] Cited for: PALMITOYLATION AT CYS-419 AND CYS-422.
[14]	"Nef induces CD4 endocytosis: requirement for a critical dileucine motif in the membrane-proximal CD4 cytoplasmic domain." Aiken C., Konner J., Landau N.R., Lenburg M.E., Trono D. Cell 76:853-864(1994) [PubMed: 8124721] [Abstract] Cited for: REMOVAL FROM CELL SURFACE BY HIV-1 NEF, MUTAGENESIS OF MET-432; SER-433; 438-LEU-LEU-439 AND SER-440.
[15]	"Cloning of ACP33 as a novel intracellular ligand of CD4." Zeitlmann L., Sirim P., Kremmer E., Kolanus W. J. Biol. Chem. 276:9123-9132(2001) [PubMed: 11113139] [Abstract] Cited for: INTERACTION WITH SPG21, MUTAGENESIS OF 457-PRO-ILE-458.
[16]	"Lipid raft distribution of CD4 depends on its palmitoylation and association with Lck, and evidence for CD4-induced lipid raft aggregation as an additional mechanism to enhance CD3 signaling." Fragoso R., Ren D., Zhang X., Su M.W., Burakoff S.J., Jin Y.J. J. Immunol. 170:913-921(2003) [PubMed: 12517957] [Abstract] Cited for: SUBCELLULAR LOCATION.
[17]	"Protein minimization of the gp120 binding region of human CD4." Sharma D., Balamurali M.M., Chakraborty K., Kumaran S., Jeganathan S., Rashid U., Ingallinella P., Varadarajan R.