Regulation of integrin-mediated adhesions

Abstract

Integrins are heterodimeric transmembrane adhesion receptors that couple the actin cytoskeleton to the extracellular environment and bidirectionally relay signals across the cell membrane. These processes are critical for cell attachment, migration, differentiation, and survival, and therefore play essential roles in metazoan development, physiology, and pathology. Integrin-mediated adhesions are regulated by diverse factors, including the conformation-specific affinities of integrin receptors for their extracellular ligands, the clustering of integrins and their intracellular binding partners into discrete adhesive structures, mechanical forces exerted on the adhesion, and the intracellular trafficking of integrins themselves. Recent advances shed light onto how the interaction of specific intracellular proteins with the short cytoplasmic tails of integrins controls each of these activities.

Figure 1. Partial summary of the major mechanisms regulating integrin-mediated cell adhesion

Talin-binding conformationally activates transmembrane integrin adhesion receptors to increase their affinity for extracellular ligand and promotes integrin clustering for high-avidity adhesions to the extracellular matrix. The talin rod domain binds actin filaments to initially enable cytoskeletal force transduction onto integrin adhesions, revealing vinculin-binding sites on talin to promote additional cytoskeletal interactions and reinforcing the adhesion, along with many additional adhesome proteins (grey circles). Both inactive and active ligand-bound integrins may be internalized by endocytic adaptor proteins (triangles) via clathrin-dependent internalization, shuttling through short-loop or long-loop endosomal recycling pathways, although clathrin-independent trafficking also occurs (not depicted).

Figure 2. Conformational Integrin Activation

On the left, the bent and inactive conformation of αIIbβ3 integrin is held in place by transmembrane interactions between the α- and β- subunits. The Outer Membrane Clasp (OMC) consists of glycine packing interactions while the Inner Membrane Clasp (IMC) uses hydrophobic stacking residues to promote the formation of an αIIb(D723)/β3(R995) salt bridge. A snorkeling β3 lysine residue produces a 25° helical tilt which embeds this helix at an angle through the membrane. On the right, conformational activation is initiated when the FERM domain of talin binds acidic lipid head groups as well as the β3-tail NPLY motif, breaking the IMC salt bridge and forming a new salt bridge between the β3 tail and talin, increasing the crossing angle of the β3 transmembrane helix and slightly extending it into the cytosol. This disengages the OMC, eliciting conformational changes in the integrin ectodomains and promoting high-affinity interactions with extracellular ligands.