Integrin Conformational Dynamics and Mechanotransduction

Abstract

The function of the integrin family of receptors as central mediators of cell-extracellular matrix (ECM) and cell-cell adhesion requires a remarkable convergence of interactions and influences. Integrins must be anchored to the cytoskeleton and bound to extracellular ligands in order to provide firm adhesion, with force transmission across this linkage conferring tissue integrity. Integrin affinity to ligands is highly regulated by cell signaling pathways, altering affinity constants by 1000-fold or more, via a series of long-range conformational transitions. In this review, we first summarize basic, well-known features of integrin conformational states and then focus on new information concerning the impact of mechanical forces on these states and interstate transitions. We also discuss how these effects may impact mechansensitive cell functions and identify unanswered questions for future studies.

Keywords: conformational activation; integrin; mechanotransduction.

Figure 1

Schematics of integrin in bent and extended conformations. (A). Integrins are non-covalent heterodimers comprised of an α subunit (blue) and a β subunit (orange). Both subunits include an extracellular region, or ectodomain, which includes the headpiece and legs, a transmembrane helix, and a cytoplasmic domain. (B). Bent and extended conformations of integrin. The α subunit (blue) consists of an N-terminal, a β-propeller, a thigh domain, two calf domains, transmembrane α helix, and cytoplasmic α tail. The α A domain is represented in gray. The β subunit (orange) consists of an N-terminal β-I domain followed by the hybrid, the plexin-semaphorin-integrin domain (PSI), four cysteine-rich epidermal growth factor (EGF) modules (I-EGF) 1-4, β-Tail domain (BTD), transmembrane β helix, and cytoplasmic β tail. (C). Ribbon representation of extended-open αIIbβ3 from cryo-EM reconstructions [24]. Secondary structure elements of the α (blue) and β (orange) subunit are shown. The α subunit seven-bladed β-propeller domain is represented in the zoomed section.

Figure 2

Reorientation of the ligand-binding interface during conformational activation of integrin αIIbβ3. (A). Ribbon representation of the platelet αIIbβ3 integrin in the bent conformation, with the ligand-binding interface (yellow, vdW representation) oriented towards the lower legs. (B,C). Ribbon representation of integrin in intermediate and extended-open conformations, with the ligand-binding interface (yellow, vdW representation) oriented away from the lower legs. The α subunit and the β subunit are represented in blue and orange, respectively. All structures are acquired from cryo-EM reconstructions of αIIbβ3 integrin [24].

Figure 3

Structure of the metal ion-binding sites of bent αIIbβ3. The metal ion binding sites correspond to the following residues: MIDAS (in pink) includes E 220, S 121, S 123, D 119, D 251; SyMBS (in cyan) includes D 217, N 215, D 158, P 219; ADMIDAS (in grey) includes D 126, D 127, M 335.

Figure 4

Effect of ECM ligand binding and pulling on integrin conformation. (A). Schematics of talin-bound integrin in extended-closed conformation. (B). Once the extended-closed conformation of integrin attaches to an ECM ligand, a membrane-normal force is exerted. (C). ECM pulling may shift the conformation to the extended-open with swing-out of the hybrid domain. A single integrin is shown here; note, however, that integrins usually function in clusters.

Figure 5

Effect of talin binding and pulling on integrin conformation. (A). Schematics of ECM-bound integrin in extended-closed conformation. (B). Once the extended-closed conformation of integrin attaches to intracellular talin, a membrane-parallel force is exerted on the β tail. (C). The connection of talin to the actin cytoskeleton provides lateral pulling of the β tail, which reorients the transmembrane β helix relative to the α helix, to induce the extended-open conformation. A single integrin is shown here; note, however, that integrins usually function in clusters.