The regulation of integrin heterodimer organisation at the reticular adhesion

Abstract

Integrins are heterodimeric transmembrane receptors with α and β subunits and play a pivotal role in mediating cell-matrix adhesion dynamics and cell migration. The activation of integrin results in conformational changes within the heterodimer and triggers the recruitment of cytoplasmic adaptor proteins that facilitates receptor oligomerizations and cytoskeletal reorganizations.

Here this study reports that the extracellular domain of β integrin, rather than the cytoplasmic domain, determines the specificity of RGD-binding integrin to reticular adhesion (RA). Compared to the conventional focal adhesion (FA), the RA exhibits a higher density of β integrin. FRET analysis also revealed the close-packed configuration of β integrin within RA.

Strikingly, integrin αV is partially depleted in a clathrin coat assembly-dependent manner. The integrin αVβ5 antibody staining also proves that integrin β5 at the clathrin coat is not in the heterodimer conformation. The suppression of clathrin lattice assembly reversed the local depletion of integrin αV. The finding of the integrin αV depletion probably breaks the conventional knowledge that mature integrins are always in heterodimer conformation.

On the vitronectin substrate, integrin β5 accumulates in RA and stably persists in the inner cell area. In contrast, integrin β3 is located at focal adhesion (FA) and regularly disassembles at the cell periphery area. During the cell migration, integrin β5 but not β3, mediates an adhesion transformation from FA to RA by adaptors recruitment. Moreover, the exchanged integrin location and persistence are shown via swapping the integrin αV-interacting domain (AID) between integrin β5 and β3. Meanwhile, the migration of the cells expressed integrin β5 or chimera with β5-AID is significantly slower than cells expressed integrin β3 or chimera with β3-AID.

In summary, this study reveals that ligand binding and clathrin coat assembly modulate intermolecular conformations between integrin subunits, regulate adhesion turnover, and orchestrate cell motility.