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First published online September 20, 2006
doi: 10.1242/10.1242/jcs.03098

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Integrin ligands at a glance

Jonathan D. Humphries^*, Adam Byron^* and Martin J. Humphries

Wellcome Trust Centre for Cell-Matrix Research, Faculty of Life Sciences, University of Manchester, Michael Smith Building, Oxford Road, Manchester, M13 9PT, UK

Author for correspondence (e-mail: martin.humphries{at}manchester.ac.uk)

	Introduction

Top Introduction Aims of this article Integrin-ligand partners Additional integrin-ligand... Lessons from evolution References

 
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 and a ß 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 subunit and 8 ß subunit genes, and to date 24 different -ß combinations have been identified at the protein level. Although some subunits appear only in a single heterodimer, 12 integrins contain the ß1 subunit, and five contain V.

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; 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

Top Introduction Aims of this article Integrin-ligand partners Additional integrin-ligand... Lessons from evolution References

 
A characteristic feature of most integrin receptors is their ability to bind a wide variety of ligands. Moreover, 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.

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	Integrin-ligand partners

Top Introduction Aims of this article Integrin-ligand partners Additional integrin-ligand... Lessons from evolution References

 
Historically, most integrin-ligand pairs have been identified either by affinity chromatography or through the ability of subunit-specific monoclonal antibodies to block adhesion of cells 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.

RGD-binding integrins
All five V integrins, two ß1 integrins (5, 8) and IIbß3 share the ability to recognise ligands containing an RGD tripeptide active site. Crystal structures of Vß3 and IIbß3 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 and ß subunits, the R residue fitting into a cleft in a ß-propeller module in the subunit, and the D coordinating a cation bound in a von Willebrand factor A-domain in the ß subunit. The RGD-binding integrins are among the most promiscuous in the family, with ß3 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 -ß active site pockets.

LDV-binding integrins
4ß1, 4ß7, 9ß1, the four members of the ß2 subfamily and Eß7 recognise related sequences in their ligands. 4ß1, 4ß7 and 9ß1 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 and ß subunits. Osteopontin also interacts with 4ß1, 4ß7 and 9ß1, but this apparently involves a different peptide motif, SVVYGLR, and the location of the ligand-binding site has not been identified.

The ß2 family employ a different mode of ligand binding, the major interaction taking place through an inserted A-domain in the subunit (see Shimaoka et al., 2003 for the structure of a complex between the L A-domain and ICAM-1). However, despite this fundamental mechanistic difference, the characterised sites within ligands that bind ß2 integrins are structurally similar to the LDV motif. The major difference is that ß1/ß7 ligands employ an aspartate residue for cation coordination whereas ß2 integrins use glutamate. Collectively, therefore, the LDV motif can be described by the consensus sequence L/I-D/E-V/S/T-P/S.

A-domain ß1 integrins
Four subunits containing an A-domain (1, 2, 10 and 11) combine with ß1 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 2 A-domain and a triple-helical collagenous peptide has revealed the structural basis of the interaction, 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.

Non-A-domain-containing laminin-binding integrins
Three ß1 integrins (3, 6 and 7), plus 6ß4, are highly selective laminin receptors. Analysis of laminin fragments indicates that these receptors and the A-domain-containing ß1 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

Top Introduction Aims of this article Integrin-ligand partners Additional integrin-ligand... Lessons from evolution References

 
As discussed above, additional integrin ligands exist that, for the sake of clarity, we do not include in the poster, even though credible evidence exists for them. These ligands, along with their respective integrin partners, are therefore listed here: ADAM family members interact with 4ß1, 5ß1, 6ß1, 9ß1, Vß3 and Vß6; COMP interacts with 5ß1 and vß3; connective tissue growth factor interacts with Vß3 and IIbß3; Cyr61 interacts with 6ß1, IIbß3, Vß3 and Dß2; E-cadherin interacts with 2ß1; ESM-1 interacts with Lß2; fibrillin interacts with 5ß1; fibrinogen interacts with Dß2; fibronectin interacts with Dß2; ICAM-4 interacts with 4ß1, Lß2, Mß2, Xß2, Vß3 and IIbß3; LAP-TGFß interacts with 8ß1 and Vß5; MMP-2 interacts with Vß3; nephronectin interacts with 8ß1; L1 interacts with 5ß1, Vß1, Vß3 and IIbß3; plasminogen interacts with Dß2; POEM interacts with 8ß1; tenascin interacts with 2ß1; thrombospondin interacts with 5ß1 and 6ß1; VEGF-C and VEGF-D interact with 9ß1; and vitronectin interacts with Dß2. Note also that both Mß2 and Xß2 interact with heparin and negative charges in denatured proteins.

	Lessons from evolution

Top Introduction Aims of this article Integrin-ligand partners Additional integrin-ligand... Lessons from evolution References

 
The model invertebrates Drosophila melanogaster and Caenorhabditis elegans have a much smaller complement of integrins than vertebrates (Hynes and Zhao, 2000). Drosophila has two ß subunits (ßPS and ß) and five subunits. ß has no known subunit partner, but ßPS combines with subunits that cluster with the laminin-binding and RGD-binding integrins. The remaining chains form a Drosophila-specific clade. A similar complement of integrins is found in Caenorhabditis elegans, which suggests 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 and five ß chain genes (Ewan et al., 2005). Two Ciona chains cluster with laminin-binding subunits and a third clusters with RGD-binding subunits. Surprisingly, eight chains contain an A-domain that is related to but, distinct from, the vertebrate A-domains. Since these subunits are expressed predominantly in blood cells, they may play a role in innate immunity. It therefore seems that collagen-binding capabilities appeared in the chordate lineage after the divergence of ascidians. Of the five Ciona ß chains, one clusters with ß1, one clusters with ß4, and three form an ascidian-specific clade.

	Acknowledgments

 
Work performed in the authors' laboratory that is related to the topic of this manuscript was supported by the Wellcome Trust. A.B. 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.

	Footnotes

 
^* These authors contributed equally to this article

	References

Top Introduction Aims of this article Integrin-ligand partners Additional integrin-ligand... Lessons from evolution References

 

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Ewan, R., Huxley-Jones, J., Mould, A. P., Humphries, M. J., Robertson, D. L. and Boot-Handford, R. P. (2005). The integrins of the urochordate Ciona intestinalis provide novel insights into the molecular evolution of the vertebrate integrin family. BMC Evol. Biol. 5, 31.[CrossRef][Medline]

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