Binding of Integrins to Laminins

Mechanisms of cell adhesion and migration rely in large part on the binding of integrin‐type cell surface receptors to extracellular matrix (ECM) macromolecule ligands. It is therefore desirable to understand the molecular details of integrin‐ECM binding. Great strides have been made in describing binding of integrins that are receptors for vasculature‐related ECM macromolecules (e.g., fibrinogen, fibronectin, vitronectin) and recognize the peptide motif RGD. In contrast, there is little information on integrins that bind to laminins (Ln), a class of ECM macromolecules predominantly found in basement membranes, neuromuscular junctions, and axon guidance paths. It is clear that Ln‐binding integrins do not recognize RGD or any linear Ln peptide motifs. To elucidate integrin‐Ln molecular mechanism of binding, we have focused on the Ln isoform Ln‐5, a major component of epithelial basement membranes. At least two integrins bind to Ln‐5: α3β1, which supports migration, and α6β4, which supports static adhesion and hemidesmosome formation. Ln‐5 interacts with these integrins through one or more of its five Ln globular (LG1‐5) domains. We previously localized one binding site for α3β1 to the LG3 domain. New data from our laboratory indicate that a second binding site for α3β1 is located on the LG4 domain and is also involved in cell adhesion and migration. We have produced LG3 and LG4 in both mammalian and bacterial expression systems, and a structure/function analysis of these domains is currently underway. We will present structural data that begin to define the molecular details of binding interactions between integrin α3β1 and LG3/LG4 domains of Ln‐5. We will discuss the possibility that two LG3/LG4 receptor binding sites on a single Ln‐5 molecule may underlie affinity/avidity regulation of α3β1 to Ln‐5.