Ligand Binding to Integrins

Abstract

The "integrin" terminology was applied in a 1987 review article (1) to describe a family of structurally, immunochemically, and functionally related cell-surface heterodimeric receptors, which integrated the extracellular matrix with the intracellular cytoskeleton to mediate cell migration and adhesion. The three original ␤ subunits (␤ 1 , ␤ 2 , and ␤ 3 ) identified have now expanded to eight, and the number of ␣ subunits stands at 17. These subunits interact noncovalently in a restricted manner to form more than 20 family members. The diversity of integrins is expanded further by alternative splicing, post-translational modifications, and interactions with other cell-surface and intracellular molecules (2-4). The number of integrins and the remarkable breadth of their cellular distribution support the statement that the phenotype of virtually every cell is uniquely influenced by its display of integrins. Over the past 13 years, more than 14,000 scientific articles have dealt with various aspects of integrin biology and almost 1,000 have appeared in the Journal of Biological Chemistry. This article examines a central aspect of integrin biology: ligand recognition and the structural basis for this function. Ligand Repertoire and RecognitionRepertoire Considerations-A hallmark of the integrins is the ability of individual family members to recognize multiple ligands. Indeed, the extent of the integrin family pales in comparison with the number of their ligands. Table I summarizes the major extracellular ligands of integrins; the listing is undoubtedly incomplete. The list includes a large number of extracellular matrix proteins (bone matrix proteins, collagens, fibronectins, fibrinogen, laminins, thrombospondins, vitronectin, and von Willebrand factor), reflecting the primary function of integrins in cell adhesion to extracellular matrices. Many "counter-receptors" are ligands, reflecting the role of integrins in mediating cell-cell interactions. Included are numerous microorganisms, which utilize integrins to gain entry into cells. There are direct and multiple linkages between integrins and host defense systems, created by their recognition of hemostatic and complement factors. The preference of any given integrin among its ligands is determined by relative affinity, availability within a specific microenvironment, and the conformational state of the ligand, which controls exposure of its integrin recognition sequence.Integrin Recognition Sequences-A primary goal of many structure-function analyses in the integrin field has been the reduction of macromolecular ligands to minimal recognition sequences. This endeavor has been highly successful, and many bioactive amino acid sequences have been teased out of large extracellular matrix proteins (5). The prototypic example is the RGD sequence. RGD was originally identified as the sequence in fibronectin that engages the fibronectin receptor, integrin ␣ 5 ␤ 1 , but now is known to serve as a recognition motif in multiple ligands for several different integrins (see Ta...

Integrin regulation of cytoplasmic calcium in excitatory neurons depends upon glutamate receptors and release from intracellular stores

“…Thus, the simplest explanation is that ligand-induced increases in cytoplasmic calcium demonstrated here are mediated by multiple ß1 integrins, including α5ß1 and αvß1 although minor contributions by other αv integrins cannot be excluded. The RGD-binding ß1 integrins are α3ß1, α5ß1, α8ß1 and αvß1 (Plow et al, 2000). This list includes integrins directly implicated in calcium regulation by the present findings: treatment with activating anti-α5ß1 or with fibronectin, a ligand for all four integrins, increased [Ca 2+ ]i. Interestingly, this list corresponds with that for integrins implicated in adult hippocampal LTP.…”

“…How brain integrins contribute to the production of stable LTP is poorly understood. Most of the integrins expressed in brain recognize an Arg-Gly-Asp (RGD) consensus sequence in their native ligands (e.g., fibronectin, vitronectin, others) (Pinkstaff et al, 1999;Plow et al, 2000). Treatment of mature hippocampal slices or synaptoneurosomes with ligand mimetic RGDpeptides or native ligands activates LTP-related kinases including calcium calmodulin protein kinase II , focal adhesion kinase (FAK), proline-rich tyrosine kinase 2 (Pyk2) and Src family kinases (Bernard-Trifilo et al, 2005).…”

Fibrinogen-Induced Increased Pial Venular Permeability in Mice

“…This contributes to an activation of ECs expressing and/or activating various integrins and adhesion molecules including ICAM-1 (Springer, 1990), a well-known Fg receptor (Plow et al, 2000). In the present study, an increase in blood Fg concentration enhanced expression of ICAM-1 in mouse brain vasculature.…”

A Role for Vascular Deficiency in Retinal Pathology in a Mouse Model of Ataxia-Telangiectasia

“…We report a significant increase in fibrinogen levels, as early as 2 months of age and ongoing to advanced stages of the disease. Increased fibrinogen content leads to its binding to endothelial receptors, intercellular adhesion molecule-1 (ICAM-1 59,60 ) and ␣5␤1 integrin. 60,61 This induces increased formation of F-actin, leading to stiffening of cells and actin filament retraction.…”