Search tips
Search criteria 


Logo of wtpaEurope PMCEurope PMC Funders GroupSubmit a Manuscript
J Cell Sci. Author manuscript; available in PMC 2012 June 21.
Published in final edited form as:
PMCID: PMC3380273


Integrin family

Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV.

Integrin function has been determined through a combination of cell biological and genetic analyses. On the cytoplasmic face of the plasma membrane, integrin occupancy coordinates the assembly of cytoskeletal polymers and signalling complexes, while on the extracellular face, integrins engage either extracellular matrix macromolecules or counter-receptors on adjacent cell surfaces. These bidirectional linkages impose spatial restrictions on signalling and extracellular matrix assembly, and thereby integrate cells with their microenvironment. In turn, membrane-proximal interactions initiate more distal functions such as tissue patterning (extracellularly) and cell fate determination (intracellularly). Genetic analyses of engineered or natural mutations have confirmed key roles for integrins in tissue integrity, cell trafficking, and differentiation (Bouvard et al., 2001; Bokel and Brown, 2002).

Aims of this article

A characteristic feature of most integrin receptors is their ability to bind a wide variety of ligands. Conversely, many extracellular matrix and cell surface adhesion proteins bind to multiple integrin receptors (Humphries, 1990; Plow et al., 2000; van der Flier and Sonnenberg, 2001). In recent years, structure-function analyses of both integrins and their ligands have revealed a similar mode of molecular interaction that explains this promiscuity. Nonetheless, the integrin literature is replete with studies describing different integrin-ligand pairs, and the major aim of this article is to provide a clarification of this picture.

The associated poster presents a cartoon representation of the major integrin-ligand combinations using hypothetical cell surfaces. We have not attempted a comprehensive cataloguing, but instead we have consulted with a number of colleagues and reached a consensus view on the best-validated integrin ligands. There are many other ligands for different integrins, the inclusion of which would overly complicate the cartoon. By citing the best studied receptor-ligand combinations, we are aware that reports from a single laboratory, or low affinity interactions (which are nonetheless functionally relevant) may be discriminated against, and for this we apologise. Some of the interactions that are supported by convincing data are nonetheless included in the text below.

Integrin-ligand partners

Historically, most integrin-ligand pairs have been identified either by affinity chromatography or through the ability of subunit-specific monoclonal antibodies to block cell adhesion to specific ligands. In some cases, direct protein-protein binding assays have been used to support biochemical or cell biological data. Despite their wide variety, it is possible to cluster integrin-ligand combinations into four main classes, reflecting the structural basis of the molecular interaction. These classes do not necessarily reflect evolutionary relationships.

(a) RGD-binding integrins

All five αV integrins, two β1 integrins (α5, α8) and αIIbβ3 share the ability to recognise ligands containing an RGD tripeptide active site. Crystal structures of αVβ3 and αIIbβ3 complexed with RGD ligands have revealed an identical atomic basis for this interaction (Xiong et al., 2002; Xiao et al., 2004). RGD binds at an interface between the α and β subunits, with the R residue fitting into a cleft in a β-propeller module in the α subunit, and the D coordinating a cation bound in a von Willebrand factor A-domain in the β subunit. The RGD-binding integrins are among the most promiscuous in the receptor family, with β3 integrins in particular binding to a large number of extracellular matrix and soluble vascular ligands. Although many ligands are shared by this subset of integrins, the rank order of ligand affinity varies, presumably reflecting the preciseness of the fit of the ligand RGD conformation with the specific α,β active site pockets.

(b) LDV-binding integrins

α4β1, α4β7, α9β1, the four members of the β2 sub-family and αEβ7 recognise related sequences in their ligands. α4β1, α4β7 and α9β1 bind to an acidic motif, termed ‘LDV’, that is functionally related to RGD. Fibronectin contains the prototype LDV ligand in its type III connecting segment region, but other ligands (such as VCAM-1 and MAdCAM-1) employ related sequences. Although definitive structural information is lacking, it is highly likely that LDV peptides bind similarly to RGD at the junction between the α and β subunits. Osteopontin also interacts with α4β1, α4β7 and α9β1, but this is apparently via a different peptide motif, SVVYGLR, and the location of the ligand-binding site has not been identified.

The β2 family employ a different mode of ligand binding, with the major interaction taking place via an inserted A-domain in the α subunit (see Shimaoka et al., 2003 for the structure of a complex between the αL A-domain and ICAM-1). However, despite this fundamental mechanistic difference, the characterised sites within ligands that bind β2 integrins are structurally homologous to the LDV motif. The major difference is that β1/β7 ligands employ an aspartate residue for cation coordination, while β2 integrins use glutamate. Collectively, therefore, the LDV motif is described by the consensus sequence L/I-D/E-V/S/T-P/S.

(c) A-domain β1 integrins

Four α subunits containing an αA-domain (α1, α2, α10 and α11) combine with β1, and form a distinct laminin/collagen-binding subfamily. Few other validated ligands have been identified for these integrins. A crystal structure of a complex between the α2 A-domain and a triple-helical collagenous peptide has revealed the structural basis of the interaction, with a critical glutamate within a collagenous GFOGER motif providing the key cation-coordinating residue (Emsley et al., 2000). Currently, the mechanism of laminin binding is unknown.

(d) Non αA-domain-containing laminin-binding integrins

Three β1 integrins (α3, α6 and α7), plus α6β4, are highly selective laminin receptors. Analysis of laminin fragments indicates that these receptors and the A-domain-containing β1 integrins bind to different regions of the ligands. In neither case has the active site been narrowed down to a particular sequence or residue.

Additional integrin-ligand interactions

As discussed above, additional integrin ligands exist that could not be included in the cartoon for the sake of clarity, even though credible evidence exists for them. These ligands, along with their respective integrin partners, are therefore listed in brief here: ADAM family members with α4β1, α5β1, α6β1, α9β1, αVβ3 and αVβ6; COMP with α5β1 and αvβ3; connective tissue growth factor with αVβ3 and αIIbβ3; Cyr61 with α6β1, αIIbβ3, αVβ3 and αDβ2; E-cadherin with α2β1; ESM-1 with αLβ2; fibrillin with α5β1; fibrinogen with αDβ2; fibronectin with αDβ2; ICAM-4 with α4β1, αLβ2, αMβ2, αXβ2, αVβ3 and αIIbβ3; LAP-TGFβ with α8β1 and αVβ5; MMP-2 with αVβ3; nephronectin with α8β1; L1 with α5β1, αVβ1,αVβ3 and αIIbβ3; plasminogen with αDβ2; POEM with α8β1; tenascin with α2β1; thrombospondin with α5β1 and α6β1; VEGF-C and VEGF-D with α9β1; and vitronectin with αDβ2. It should also be noted that both αMβ2 and αXβ2 interact with heparin and negative charges in denatured proteins.

Lessons from evolution

The model invertebrates, Drosophila melanogaster and Caenorhabditis elegans, have a much smaller complement of integrins than vertebrates (Hynes and Zhao, 2000). Drosophila has two β subunits (βPS and βν) and five α subunits. βν has no known α subunit partner, but βPS combines with subunits that cluster with the laminin-binding and RGD-binding integrins. The remaining An external file that holds a picture, illustration, etc.
Object name is ukmss-47674-ig0002.jpg chains form a Drosophila-specific clade. A similar complement of integrins is found for Caenorhabditis elegans, suggesting that the earliest metazoans possessed two primordial integrins, one laminin-specific and one RGD ligand-specific.

The genome of the early chordate Ciona intestinalis encodes eleven α and five β chain genes (Ewan et al., 2005). Two Ciona α chains cluster with laminin-binding subunits and a third clusters with RGD-binding subunits. Surprisingly, eight α chains contain an αA-domain that is related to but, distinct from, the vertebrate αA-domains. As these subunits are expressed predominantly in blood cells, they may play a role in innate immunity. It therefore appears that collagen-binding capabilities occurred in the chordate lineage after the divergence of ascidians. Of the five Ciona β chains, one clusters with β1, one with β4, and three form an ascidian-specific clade.


Work performed in the authors’ laboratory that is related to the topic of this manuscript was supported by the Wellcome Trust. Adam Byron is supported by a BBSRC CASE PhD studentship, sponsored by GlaxoSmithKline. We thank Dean Sheppard, Nancy Hogg, Tim Springer, Mark Ginsberg and Steve Ludbrook for their comments on ligand specificities of different integrin subsets.


  • Arnaout MA, Mahalingam B, Xiong JP. Integrin structure, allostery, and bidirectional signaling. Annu. Rev. Cell Dev. Biol. 2005;21:381–410. [PubMed]
  • Bokel C, Brown NH. Integrins in development: moving on, responding to, and sticking to the extracellular matrix. Dev. Cell. 2002;3:311–321. [PubMed]
  • Bouvard D, Brakebusch C, Gustafsson E, Aszodi A, Bengtsson T, Berna A, Fassler R. Functional consequences of integrin gene mutations in mice. Circ. Res. 2001;89:211–223. [PubMed]
  • Emsley J, Knight CG, Farndale RW, Barnes MJ, Liddington RC. Structural basis of collagen recognition by integrin alpha2beta1. Cell. 2000;101:47–56. [PubMed]
  • Ewan R, Huxley-Jones J, Mould AP, Humphries MJ, Robertson DL, Boot-Handford RP. The integrins of the urochordate Ciona intestinalis provide novel insights into the molecular evolution of the vertebrate integrin family. BMC Evol. Biol. 2005;5:31. [PMC free article] [PubMed]
  • Humphries MJ. The molecular basis and specificity of integrin-ligand interactions. J. Cell Sci. 1990;97:585–592. [PubMed]
  • Humphries MJ. Integrin structure. Biochem. Soc. Trans. 2000;28:311–339. [PubMed]
  • Hynes RO. Integrins: bidirectional, allosteric signaling machines. Cell. 2002;110:673–687. [PubMed]
  • Hynes RO, Zhao Q. The evolution of cell adhesion. J. Cell Biol. 2000;150:F89–F96. [PMC free article] [PubMed]
  • Plow EF, Haas TA, Zhang L, Loftus J, Smith JW. Ligand binding to integrins. J. Biol. Chem. 2000;275:21785–21788. [PubMed]
  • Shimaoka M, Xiao T, Liu JH, Yang Y, Dong Y, Jun CD, McCormack A, Zhang R, Joachimiak A, Takagi J, Wang JH, Springer TA. Structures of the alpha L I domain and its complex with ICAM-1 reveal a shape-shifting pathway for integrin regulation. Cell. 2003;112:99–111. [PubMed]
  • Springer TA, Wang JH. The three-dimensional structure of integrins and their ligands, and conformational regulation of cell adhesion. Adv Protein Chem. 2004;68:29–63. [PubMed]
  • van der Flier A, Sonnenberg A. Function and interactions of integrins. Cell Tissue Res. 2001;305:285–298. [PubMed]
  • Xiao T, Takagi J, Coller BS, Wang JH, Springer TA. Structural basis for allostery in integrins and binding to fibrinogen-mimetic therapeutics. Nature. 2004;432:59–67. [PubMed]
  • Xiong JP, Stehle T, Zhang R, Joachimiak A, Frech M, Goodman SL, Arnaout MA. Crystal structure of the extracellular segment of integrin alpha Vbeta3 in complex with an Arg-Gly-Asp ligand. Science. 2002;296:151–155. [PubMed]