Integrin alpha-4
Also known as: CD49D, ITGA4
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. ITGA4:ITGB1 binds to fractalkine (CX3CL1) and may act as its coreceptor in CX3CR1-dependent fractalkine signaling. ITGA4:ITGB1 binds to PLA2G2A via a site (site 2) which is distinct from the classical ligand-binding site (site 1) and this induces integrin conformational changes and enhanced ligand binding to site 1. Integrin ITGA4:ITGB1 represses PRKCA-mediated L-type voltage-gated channel Ca(2+) influx and ROCK-mediated calcium sensitivity in vascular smooth muscle cells via its interaction with SVEP1, thereby inhibiting vasocontraction.
Classification
- Family (Pfam)
- PF01839 FG-GAP, PF08441 Integrin_A_Ig_1, PF20805 Integrin_A_Ig_2, PF20806 Integrin_A_Ig_3
- InterPro
- FG-GAP, Int_alpha_beta-p, Integrin_alpha, Integrin_alpha_C_CS, Integrin_alpha_Ig-like_1, Integrin_alpha_Ig-like_2, Integrin_alpha_Ig-like_3, Integrin_alpha_N, Integrin_dom_sf
- Functional cluster
- Immunoglobulin-Domain Cell Adhesion Proteins
Experimental structures · PDB · 7
- 3V4P X-ray 3.15A
- 3V4V X-ray 3.10A
- 4HKC X-ray 2.20A
- 5C7Z X-ray 2.77A
- 5FPI X-ray 2.77A
- 9P95 EM 3.05A
- 9P96 EM 3.10A
A predicted model is available from AlphaFold.
Gene Ontology · 40
- GO:0009986 cell surface
- GO:0070062 extracellular exosome
- GO:0005925 focal adhesion
- GO:0030426 growth cone
- GO:0034668 integrin alpha4-beta1 complex
- GO:0034669 integrin alpha4-beta7 complex
- GO:0016020 membrane
- GO:0043025 neuronal cell body
- GO:0005886 plasma membrane
- GO:0050839 cell adhesion molecule binding
- GO:0015026 coreceptor activity
- GO:0001968 fibronectin binding
- GO:0005178 integrin binding
- GO:0046872 metal ion binding
- GO:1990405 protein antigen binding
- GO:0038023 signaling receptor activity
- GO:0060385 axonogenesis involved in innervation
- GO:0030183 B cell differentiation
- GO:0098609 cell-cell adhesion
- GO:0033631 cell-cell adhesion mediated by integrin
- GO:0007160 cell-matrix adhesion
- GO:0003366 cell-matrix adhesion involved in ameboidal cell migration
- GO:1904646 cellular response to amyloid-beta
- GO:0071345 cellular response to cytokine stimulus
- GO:1990771 clathrin-dependent extracellular exosome endocytosis
- GO:0050904 diapedesis
- GO:0035987 endodermal cell differentiation
- GO:0034113 heterotypic cell-cell adhesion
- GO:0002387 immune response in gut-associated lymphoid tissue
- GO:0007229 integrin-mediated signaling pathway
- GO:0007159 leukocyte cell-cell adhesion
- GO:0050901 leukocyte tethering or rolling
- GO:0045906 negative regulation of vasoconstriction
- GO:1990138 neuron projection extension
- GO:2000353 positive regulation of endothelial cell apoptotic process
- GO:1903238 positive regulation of leukocyte tethering or rolling
- GO:2000406 positive regulation of T cell migration
- GO:1905564 positive regulation of vascular endothelial cell proliferation
- GO:0043113 receptor clustering
- GO:0034446 substrate adhesion-dependent cell spreading
Drugs targeting this protein · 2
- FIRATEGRAST antagonist
- UCB-1184197 inhibitor
Related proteins · sequence + function similarity
- Integrin alpha-4 0.98
- Integrin alpha-9 0.94
- Integrin alpha-9 0.93
- Integrin alpha-4 0.92
- Integrin alpha-8 0.90
- Integrin alpha-8 0.88
- Integrin alpha-8 0.87
- Integrin alpha-1 0.86
- Integrin alpha-1 0.86
- Integrin alpha-6 0.86
- Integrin alpha-6 0.85
- Integrin alpha-6 0.85
Co-cited proteins · studied together in the literature
- Basal cell adhesion molecule 1 shared papers
- Chondroitin sulfate proteoglycan 4 1 shared papers
- Integrin beta-1 8 shared papers
- Junctional adhesion molecule-like 1 shared papers
- Integrin alpha-5 4 shared papers
- Integrin alpha-3 1 shared papers
- Leupaxin 1 shared papers
- Phospholipase A2, membrane associated 2 shared papers
- Integrin alpha-4 1 shared papers
- Integrin alpha-V 4 shared papers
- Paxillin 1 shared papers
- Integrin beta-3 4 shared papers
Literature · 23 cited papers
- The C-type lectin domain of CD62P (P-selectin) functions as an integrin ligand. Life. Sci Alliance · 2023
- The integrin ligand SVEP1 regulates GPCR-mediated vasoconstriction via integrins alpha9beta1 and alpha4beta1. Br. J. Pharmacol. · 2022
- N-terminome analysis of the human mitochondrial proteome. Proteomics · 2015
- Proinflammatory secreted phospholipase A2 type IIA (sPLA-IIA) induces integrin activation through direct binding to a newly identified binding site (site 2) in integrins alphavbeta3, alpha4beta1, and alpha5beta1. J. Biol. Chem. · 2015
- An enzyme assisted RP-RPLC approach for in-depth analysis of human liver phosphoproteome. J. Proteomics · 2014
- Integrins alphavbeta3 and alpha4beta1 act as coreceptors for fractalkine, and the integrin-binding defective mutant of fractalkine is an antagonist of CX3CR1. J. Immunol. · 2012
- Quantitative phosphoproteomic analysis of T cell receptor signaling reveals system-wide modulation of protein-protein interactions. Sci. Signal. · 2009
- Mass-spectrometric identification and relative quantification of N-linked cell surface glycoproteins. Nat. Biotechnol. · 2009
- JAM-L-mediated leukocyte adhesion to endothelial cells is regulated in cis by alpha4beta1 integrin activation. J. Cell Biol. · 2008
- Pro-inflammatory secretory phospholipase A2 type IIA binds to integrins alphavbeta3 and alpha4beta1 and induces proliferation of monocytic cells in an integrin-dependent manner. J. Biol. Chem. · 2008
- Endothelial Lu/BCAM glycoproteins are novel ligands for red blood cell alpha4beta1 integrin: role in adhesion of sickle red blood cells to endothelial cells. Blood · 2007
- Generation and annotation of the DNA sequences of human chromosomes 2 and 4. Nature · 2005
- … and 11 more in the literature graph