Structural mechanism of integrin inactivation by filamin

Abstract

The activation of heterodimeric (α/β) integrin is crucial for regulating cell adhesion. Binding of talin to the cytoplasmic face of integrin activates the receptor, but how integrin is properly maintained in resting state to counterbalance its activation for regulating adhesion dynamics remains obscure. We report the structure of cytoplasmic domain of human integrin αIIbβ3 bound to its inhibitor, the immunoglobin repeat 21 of filamin A (FLNa-Ig21). The structure reveals an unexpected ternary complex where FLNa-Ig21 not only binds to previously predicted C-terminus of integrin β3 cytoplasmic tail (CT) but also engages N-terminal helices of αIIb and β3 CTs to stabilize an inter-CT clasp that helps restrain the integrin in a resting state. Combined with functional data, the structure reveals a novel mechanism of filamin-mediated retention of inactive integrin, suggesting a new framework for understanding regulation of integrin activation and adhesion.

Binding of Myomesin to Obscurin-Like-1 at the Muscle M-Band Provides a Strategy for Isoform-Specific Mechanical Protection

“…Filamin A can interact with the cytoplasmic tail of integrin 3 via its Ig-like domain 21 (FLNa21), but FLNa21 can also bind to the linker between FLNa20 and 21 in an intramolecular complex that competes with integrin. Intriguingly, the removal of the trans -complemented β-strand from FLNa21 unmasks the binding site for integrin, which, when bound to filamin, engages integrin an inactive state (Heikkinen et al., 2009, Liu et al., 2015). This specific interaction can be opened by mechanical stretch and triggers integrin binding, filamin's partner in mechanosensing (Chen et al., 2009, Seppala et al., 2015).…”

RSK2 activity mediates glioblastoma invasiveness and is a potential target for new therapeutics

“…It does so in part by phosphorylating its target FLNa, a negative regulator of integrin activation [36, 47], and promoting FLNa association with the integrin cytoplasmic tails. We now find that RSK2 alters adhesion and migration in GBM cells.…”

Phosphorylation of filamin A regulates chemokine receptor CCR2 recycling

“…Also consistent with this view, the actin-binding site of FLNa that is responsible for its actin cross-linking activity was not required to sustain efficient recycling of CCR2B and β2AR. Based on our current observations and previous data demonstrating that FLNa interacts with several chemokine receptors and integrins (Liu et al, 2015), which follow the same path to the plasma membrane, we propose that FLNa works as a receptor scaffold that links cargo directly or indirectly to actin microdomains in the sorting endosome. We found that this FLNa function is regulated by its phosphorylation at S2152, which, in turn, is promoted by GPCR-signaling to second messenger kinases.…”