Physical Chemistry Seminar
20 April

The inner life of adhesion sites: deciphering the molecular ballet in integrin-based adhesions

Le 20 April - 11h-12h

Integrin-based focal adhesions (FAs) initiate chemical and mechanical signals involved in cell polarity, migration, proliferation and differentiation. Super-resolution microscopy revealed that FAs are organized at the nanoscale into functional layers from the lower plasma membrane to the upper actin cytoskeleton. Among the main partners of integrin adhesion receptors, talin and kindlin are two essential integrin activators cooperating to ensure full integrin activation for cell spreading and adhesion. Yet, how FAs proteins are guided into specific nano-layers to promote interaction with given targets is unknown. 
Using single protein tracking, superresolution microscopy and functional assays, we link the molecular behavior and 3D nanoscale localization of integrin, talin and kindlin with their function in integrin activation inside FAs. We show that kindlin efficient interaction with integrins inside FAs could not result from its cytosolic diffusion alone, but requires kindlin membrane diffusion to drive kindlin in the proper FAs functional layer. We show that immobilization of integrins in FAs depends on interaction with kindlin and talin. Unlike talin, kindlin displays free diffusion along the plasma membrane outside and inside FAs. We demonstrate that the kindlin Pleckstrin Homology domain promotes membrane diffusion and localization to the membrane-proximal integrin nano-layer, necessary for kindlin enrichment and function in FAs. Using kindlin-deficient cells, we show that kindlin membrane localization and diffusion are crucial for integrin activation, cell spreading and FAs formation. To conclude, kindlin uses a different route than talin to reach and activate integrins, providing a possible molecular basis for their complementarity during integrin activation. 
Thus our study reveals that the molecular dynamical behavior of a protein in a subcellular compartment is directly linked to its function. It emphasizes the particular importance for cell biology to decipher how thermal stochastic motions of proteins are converted by specific biochemical interactions into a specific route enabling protein access to particular location or functional nanolayers/domains.

At Amhi Curie and on TEAMS

IINS - Interdisciplinary Institute for Neurosciences UMR5297 CNRS/Univ. Bordeaux
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