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P13612 (ITA4_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Last modified July 9, 2014. Version 155. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (7) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Interactions·Sequence annotation·Sequences·References·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
Integrin alpha-4
Alternative name(s):
CD49 antigen-like family member D
Integrin alpha-IV
VLA-4 subunit alpha
CD_antigen=CD49d
Gene names
Name:ITGA4
Synonyms:CD49D
OrganismHomo sapiens (Human) [Reference proteome]
Taxonomic identifier9606 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo

Protein attributes

Sequence length1032 AA.
Sequence statusComplete.
Sequence processingThe displayed sequence is further processed into a mature form.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

Integrins alpha-4/beta-1 (VLA-4) and alpha-4/beta-7 are receptors for fibronectin. They recognize one or more domains within the alternatively spliced CS-1 and CS-5 regions of fibronectin. They are also receptors for VCAM1. Integrin alpha-4/beta-1 recognizes the sequence Q-I-D-S in VCAM1. Integrin alpha-4/beta-7 is also a receptor for MADCAM1. It recognizes the sequence L-D-T in MADCAM1. On activated endothelial cells integrin VLA-4 triggers homotypic aggregation for most VLA-4-positive leukocyte cell lines. It may also participate in cytolytic T-cell interactions with target cells. Ref.12

Subunit structure

Heterodimer of an alpha and a beta subunit. The alpha subunit can sometimes be cleaved into two non-covalently associated fragments. Alpha-4 associates with either beta-1 or beta-7. Alpha-4 interacts with PXN, LPXN, and TGFB1I1/HIC5. Interacts with CSPG4 through CSPG4 chondroitin sulfate glycosaminoglycan. Interacts with AMICA1; integrin alpha-4/beta-1 may regulate leukocyte to endothelial cells adhesion by controlling AMICA1 homodimerization. Ref.9 Ref.10 Ref.12

Subcellular location

Membrane; Single-pass type I membrane protein.

Domain

The SG1 motif is involved in binding to chondroitin sulfate glycosaminoglycan and cell adhesion. Ref.9

Post-translational modification

Phosphorylation on Ser-1027 inhibits PXN binding.

Sequence similarities

Belongs to the integrin alpha chain family.

Contains 7 FG-GAP repeats.

Sequence caution

The sequence AAB59613.1 differs from that shown. Reason: Frameshift at position 13.

The sequence CAA34852.1 differs from that shown. Reason: Frameshift at position 13.

Ontologies

Keywords
   Biological processCell adhesion
   Cellular componentMembrane
   Coding sequence diversityPolymorphism
   DomainRepeat
Signal
Transmembrane
Transmembrane helix
   LigandCalcium
Metal-binding
   Molecular functionIntegrin
Receptor
   PTMDisulfide bond
Glycoprotein
Phosphoprotein
   Technical term3D-structure
Complete proteome
Direct protein sequencing
Reference proteome
Gene Ontology (GO)
   Biological_processB cell differentiation

Inferred by curator PubMed 1715889. Source: BHF-UCL

blood coagulation

Traceable author statement. Source: Reactome

blood vessel remodeling

Inferred from electronic annotation. Source: Ensembl

chorio-allantoic fusion

Inferred from electronic annotation. Source: Ensembl

extracellular matrix organization

Traceable author statement. Source: Reactome

face development

Inferred from electronic annotation. Source: Ensembl

heart development

Inferred from electronic annotation. Source: Ensembl

heterophilic cell-cell adhesion

Inferred from electronic annotation. Source: Ensembl

integrin-mediated signaling pathway

Inferred from electronic annotation. Source: UniProtKB-KW

leukocyte cell-cell adhesion

Inferred from direct assay PubMed 1715889. Source: BHF-UCL

leukocyte migration

Traceable author statement. Source: Reactome

negative regulation of protein homodimerization activity

Inferred from direct assay PubMed 12869515. Source: UniProtKB

regulation of immune response

Traceable author statement. Source: Reactome

   Cellular_componentcell surface

Inferred from direct assay PubMed 1715889. Source: BHF-UCL

external side of plasma membrane

Inferred from electronic annotation. Source: Ensembl

extracellular vesicular exosome

Inferred from direct assay PubMed 12519789. Source: UniProtKB

integrin complex

Inferred from electronic annotation. Source: InterPro

plasma membrane

Inferred from direct assay PubMed 12869515. Source: UniProtKB

   Molecular_functioncell adhesion molecule binding

Inferred from physical interaction PubMed 12869515. Source: UniProtKB

metal ion binding

Inferred from electronic annotation. Source: UniProtKB-KW

protein binding

Inferred from physical interaction PubMed 9079671. Source: UniProtKB

Complete GO annotation...

Binary interactions

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Signal peptide1 – 3333 Ref.7
Chain34 – 1032999Integrin alpha-4
PRO_0000016244

Regions

Topological domain35 – 977943Extracellular Potential
Transmembrane978 – 100124Helical; Potential
Topological domain1002 – 103231Cytoplasmic Potential
Repeat35 – 10066FG-GAP 1
Repeat110 – 17768FG-GAP 2
Repeat185 – 23753FG-GAP 3
Repeat238 – 29356FG-GAP 4
Repeat294 – 35158FG-GAP 5
Repeat355 – 41258FG-GAP 6
Repeat416 – 47863FG-GAP 7
Calcium binding314 – 3229 Potential
Calcium binding377 – 3859 Potential
Calcium binding439 – 4479 Potential
Motif606 – 61611SG1
Motif1003 – 10075GFFKR motif

Sites

Site591 – 5922Cleavage

Amino acid modifications

Modified residue10211Phosphoserine Ref.11 Ref.14
Glycosylation791N-linked (GlcNAc...) Potential
Glycosylation1381N-linked (GlcNAc...) Potential
Glycosylation2291N-linked (GlcNAc...) Potential
Glycosylation4801N-linked (GlcNAc...) Ref.13
Glycosylation5181N-linked (GlcNAc...) Ref.13
Glycosylation5381N-linked (GlcNAc...) Ref.13
Glycosylation6261N-linked (GlcNAc...) Potential
Glycosylation6451N-linked (GlcNAc...) Ref.13
Glycosylation6601N-linked (GlcNAc...) Potential
Glycosylation8061N-linked (GlcNAc...) Potential
Glycosylation8211N-linked (GlcNAc...) Potential
Disulfide bond91 ↔ 101 By similarity
Disulfide bond144 ↔ 165 By similarity
Disulfide bond183 ↔ 198 By similarity
Disulfide bond486 ↔ 495 By similarity
Disulfide bond501 ↔ 557 By similarity
Disulfide bond622 ↔ 627 By similarity
Disulfide bond698 ↔ 711 By similarity
Disulfide bond852 ↔ 890 By similarity
Disulfide bond897 ↔ 902 By similarity

Natural variations

Natural variant6341S → T.
Corresponds to variant rs35322532 [ dbSNP | Ensembl ].
VAR_047423
Natural variant8241V → A.
Corresponds to variant rs1143675 [ dbSNP | Ensembl ].
VAR_047424
Natural variant8781R → Q. Ref.3 Ref.5
Corresponds to variant rs1143676 [ dbSNP | Ensembl ].
VAR_003978

Experimental info

Mutagenesis5901K → Q: Abolishes almost completely cleavage. Ref.8
Mutagenesis5911R → L: Abolishes completely cleavage. Ref.8
Mutagenesis10211S → A: Abolishes phosphorylation. Ref.11
Mutagenesis10211S → D: Reduces PXN binding. Ref.11
Mutagenesis10241Y → A: Disrupts PXN binding. Ref.10

Secondary structure

................................................................................................. 1032
Helix Strand Turn

Details...

Sequences

Sequence LengthMass (Da)Tools
P13612 [UniParc].

Last modified November 2, 2010. Version 3.
Checksum: 73EC1204DE78CD35

FASTA1,032114,900
        10         20         30         40         50         60 
MAWEARREPG PRRAAVRETV MLLLCLGVPT GRPYNVDTES ALLYQGPHNT LFGYSVVLHS 

        70         80         90        100        110        120 
HGANRWLLVG APTANWLANA SVINPGAIYR CRIGKNPGQT CEQLQLGSPN GEPCGKTCLE 

       130        140        150        160        170        180 
ERDNQWLGVT LSRQPGENGS IVTCGHRWKN IFYIKNENKL PTGGCYGVPP DLRTELSKRI 

       190        200        210        220        230        240 
APCYQDYVKK FGENFASCQA GISSFYTKDL IVMGAPGSSY WTGSLFVYNI TTNKYKAFLD 

       250        260        270        280        290        300 
KQNQVKFGSY LGYSVGAGHF RSQHTTEVVG GAPQHEQIGK AYIFSIDEKE LNILHEMKGK 

       310        320        330        340        350        360 
KLGSYFGASV CAVDLNADGF SDLLVGAPMQ STIREEGRVF VYINSGSGAV MNAMETNLVG 

       370        380        390        400        410        420 
SDKYAARFGE SIVNLGDIDN DGFEDVAIGA PQEDDLQGAI YIYNGRADGI SSTFSQRIEG 

       430        440        450        460        470        480 
LQISKSLSMF GQSISGQIDA DNNGYVDVAV GAFRSDSAVL LRTRPVVIVD ASLSHPESVN 

       490        500        510        520        530        540 
RTKFDCVENG WPSVCIDLTL CFSYKGKEVP GYIVLFYNMS LDVNRKAESP PRFYFSSNGT 

       550        560        570        580        590        600 
SDVITGSIQV SSREANCRTH QAFMRKDVRD ILTPIQIEAA YHLGPHVISK RSTEEFPPLQ 

       610        620        630        640        650        660 
PILQQKKEKD IMKKTINFAR FCAHENCSAD LQVSAKIGFL KPHENKTYLA VGSMKTLMLN 

       670        680        690        700        710        720 
VSLFNAGDDA YETTLHVKLP VGLYFIKILE LEEKQINCEV TDNSGVVQLD CSIGYIYVDH 

       730        740        750        760        770        780 
LSRIDISFLL DVSSLSRAEE DLSITVHATC ENEEEMDNLK HSRVTVAIPL KYEVKLTVHG 

       790        800        810        820        830        840 
FVNPTSFVYG SNDENEPETC MVEKMNLTFH VINTGNSMAP NVSVEIMVPN SFSPQTDKLF 

       850        860        870        880        890        900 
NILDVQTTTG ECHFENYQRV CALEQQKSAM QTLKGIVRFL SKTDKRLLYC IKADPHCLNF 

       910        920        930        940        950        960 
LCNFGKMESG KEASVHIQLE GRPSILEMDE TSALKFEIRA TGFPEPNPRV IELNKDENVA 

       970        980        990       1000       1010       1020 
HVLLEGLHHQ RPKRYFTIVI ISSSLLLGLI VLLLISYVMW KAGFFKRQYK SILQEENRRD 

      1030 
SWSYINSKSN DD 

« Hide

References

« Hide 'large scale' references
[1]"The primary structure of the alpha 4 subunit of VLA-4: homology to other integrins and a possible cell-cell adhesion function."
Takada Y., Elices M.J., Crouse C., Hemler M.E.
EMBO J. 8:1361-1368(1989) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[2]"A single mRNA encodes the alpha 150 and alpha 80/70 forms of the alpha subunit of VLA4."
Rubio M., Nueda A., Vara A., Corbi-Lopez A.L.
Eur. J. Immunol. 22:1099-1102(1992) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[3]"Identification of two variants of the human integrin alpha 4 subunit."
Szabo M.C., McIntyre B.W.
Mol. Immunol. 32:1453-1454(1995) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA], VARIANT GLN-878.
[4]"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. expand/collapse author list , 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].
[5]Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., Turner R. expand/collapse author list , Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W., Venter J.C.
Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA], VARIANT GLN-878.
[6]"Characterization of the alpha 4 integrin gene promoter."
Rosen G.D., Birkenmeier T.M., Dean D.C.
Proc. Natl. Acad. Sci. U.S.A. 88:4094-4098(1991) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 1-87.
[7]"The very late antigen family of heterodimers is part of a superfamily of molecules involved in adhesion and embryogenesis."
Takada Y., Strominger J.L., Hemler M.E.
Proc. Natl. Acad. Sci. U.S.A. 84:3239-3243(1987) [PubMed] [Europe PMC] [Abstract]
Cited for: PROTEIN SEQUENCE OF 34-47.
[8]"Functional and structural analysis of VLA-4 integrin alpha 4 subunit cleavage."
Teixido J., Parker C.M., Kassner P.D., Hemler M.E.
J. Biol. Chem. 267:1786-1791(1992) [PubMed] [Europe PMC] [Abstract]
Cited for: PROTEIN SEQUENCE OF 592-601, PROTEOLYTIC PROCESSING, MUTAGENESIS OF LYS-590 AND ARG-591.
[9]"A role of chondroitin sulfate glycosaminoglycan binding site in alpha4beta1 integrin-mediated melanoma cell adhesion."
Iida J., Meijne A.M.L., Oegema T.R. Jr., Yednock T.A., Kovach N.L., Furcht L.T., McCarthy J.B.
J. Biol. Chem. 273:5955-5962(1998) [PubMed] [Europe PMC] [Abstract]
Cited for: DOMAIN, INTERACTION WITH CSPG4.
[10]"Binding of paxillin to alpha4 integrins modifies integrin-dependent biological responses."
Liu S., Thomas S.M., Woodside D.G., Rose D.M., Kiosses W.B., Pfaff M., Ginsberg M.H.
Nature 402:676-681(1999) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH PXN; LPXN AND TGFB1I1, MUTAGENESIS OF TYR-1024.
[11]"Phosphorylation of the integrin alpha 4 cytoplasmic domain regulates paxillin binding."
Han J., Liu S., Rose D.M., Schlaepfer D.D., McDonald H., Ginsberg M.H.
J. Biol. Chem. 276:40903-40909(2001) [PubMed] [Europe PMC] [Abstract]
Cited for: PHOSPHORYLATION AT SER-1021, MUTAGENESIS OF SER-1021.
[12]"JAM-L-mediated leukocyte adhesion to endothelial cells is regulated in cis by alpha4beta1 integrin activation."
Luissint A.C., Lutz P.G., Calderwood D.A., Couraud P.O., Bourdoulous S.
J. Cell Biol. 183:1159-1173(2008) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN LEUKOCYTE TO ENDOTHELIAL CELLS ADHESION, INTERACTION WITH AMICA1.
[13]"Mass-spectrometric identification and relative quantification of N-linked cell surface glycoproteins."
Wollscheid B., Bausch-Fluck D., Henderson C., O'Brien R., Bibel M., Schiess R., Aebersold R., Watts J.D.
Nat. Biotechnol. 27:378-386(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-480; ASN-518; ASN-538 AND ASN-645.
Tissue: Leukemic T-cell.
[14]"Quantitative phosphoproteomic analysis of T cell receptor signaling reveals system-wide modulation of protein-protein interactions."
Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K., Rodionov V., Han D.K.
Sci. Signal. 2:RA46-RA46(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-1021, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
Tissue: Leukemic T-cell.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
X16983 mRNA. Translation: CAA34852.1. Frameshift.
L12002 mRNA. Translation: AAB59613.1. Frameshift.
AC020595 Genomic DNA. No translation available.
CH471058 Genomic DNA. Translation: EAX10985.1.
CH471058 Genomic DNA. Translation: EAX10987.1.
CCDSCCDS42788.1.
PIRS06046.
RefSeqNP_000876.3. NM_000885.4.
UniGeneHs.440955.

3D structure databases

PDBe
RCSB-PDB
PDBj
EntryMethodResolution (Å)ChainPositionsPDBsum
3V4PX-ray3.15A/C34-620[»]
3V4VX-ray3.10A/C34-620[»]
4HKCX-ray2.20B1003-1032[»]
ProteinModelPortalP13612.
SMRP13612. Positions 34-829, 976-1015.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid109883. 497 interactions.
DIPDIP-34971N.
IntActP13612. 10 interactions.
MINTMINT-4098849.
STRING9606.ENSP00000380227.

Chemistry

BindingDBP13612.
ChEMBLCHEMBL1907599.
DrugBankDB00108. Natalizumab.
GuidetoPHARMACOLOGY2443.

PTM databases

PhosphoSiteP13612.

Polymorphism databases

DMDM311033436.

Proteomic databases

MaxQBP13612.
PaxDbP13612.
PRIDEP13612.

Protocols and materials databases

DNASU3676.
StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENST00000397033; ENSP00000380227; ENSG00000115232.
GeneID3676.
KEGGhsa:3676.
UCSCuc002unu.3. human.

Organism-specific databases

CTD3676.
GeneCardsGC02P182285.
HGNCHGNC:6140. ITGA4.
MIM192975. gene.
neXtProtNX_P13612.
PharmGKBPA29940.
GenAtlasSearch...

Phylogenomic databases

eggNOGNOG324320.
HOGENOMHOG000088626.
HOVERGENHBG004538.
InParanoidP13612.
KOK06483.
OMANRRDSWS.
OrthoDBEOG7MSMN4.
PhylomeDBP13612.
TreeFamTF105391.

Enzyme and pathway databases

ReactomeREACT_118779. Extracellular matrix organization.
REACT_604. Hemostasis.
REACT_6900. Immune System.
SignaLinkP13612.

Gene expression databases

ArrayExpressP13612.
BgeeP13612.
CleanExHS_ITGA4.
GenevestigatorP13612.

Family and domain databases

InterProIPR013517. FG-GAP.
IPR013519. Int_alpha_beta-p.
IPR000413. Integrin_alpha.
IPR013649. Integrin_alpha-2.
IPR018184. Integrin_alpha_C_CS.
[Graphical view]
PfamPF01839. FG-GAP. 2 hits.
PF08441. Integrin_alpha2. 1 hit.
[Graphical view]
PRINTSPR01185. INTEGRINA.
SMARTSM00191. Int_alpha. 5 hits.
[Graphical view]
PROSITEPS51470. FG_GAP. 7 hits.
PS00242. INTEGRIN_ALPHA. 1 hit.
[Graphical view]
ProtoNetSearch...

Other

ChiTaRSITGA4. human.
GeneWikiCD49d.
GenomeRNAi3676.
NextBio14391.
PROP13612.
SOURCESearch...

Entry information

Entry nameITA4_HUMAN
AccessionPrimary (citable) accession number: P13612
Secondary accession number(s): D3DPG4
Entry history
Integrated into UniProtKB/Swiss-Prot: January 1, 1990
Last sequence update: November 2, 2010
Last modified: July 9, 2014
This is version 155 of the entry and version 3 of the sequence. [Complete history]
Entry statusReviewed (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.

Relevant documents

SIMILARITY comments

Index of protein domains and families

PDB cross-references

Index of Protein Data Bank (PDB) cross-references

MIM cross-references

Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot

Human polymorphisms and disease mutations

Index of human polymorphisms and disease mutations

Human entries with polymorphisms or disease mutations

List of human entries with polymorphisms or disease mutations

Human chromosome 2

Human chromosome 2: entries, gene names and cross-references to MIM

Human cell differentiation molecules

CD nomenclature of surface proteins of human leucocytes and list of entries