Deciphering how the geometrical and mechanical context impacts actin filament disassembly

In an article recently published in P.N.A.S., researchers from the “Regulation of Actin Assembly Dynamics” team at Institut Jacques Monod show how the biochemical disassembly of actin filaments can be modulated by their physical context.

Actin filaments form a variety of networks in cells, where they are responsible for a number of essential functions. These filament networks are dynamic and have to be built and disassembled in a controlled manner. The main proteins in charge of disassembly are the proteins of the ADF/cofilin family, which bind to the sides of filaments to sever them, and promote the depolymerization of the resulting fragments. Most of what we know about this molecular mechanism was determined thanks to in vitro experiments, and in particular thanks to observations carried out on individual filaments. In these experiments, the filaments are usually floating freely in solution, which is very different from the cell context where filaments are interconnected and exposed to various forces (such as tension and bending). Here, thanks to an original microfluidics setup, we have studied how geometrical constraints and mechanical stresses affect the action of ADF/cofilin. We find that bent filaments are easier to break, while tension has almost no effect. Most strikingly, we find that interconnected filaments are a lot easier to fragment than free filaments. The reason comes from the already known fact that ADF/cofilin, as it binds to an actin filament, locally changes the filament’s helical pitch. We show that, as a consequence, when binding to a filament segment between two anchoring points, ADF/cofilin applies a mechanical torque on the filament, thereby enhancing its severing rate up to 100-fold. We further show that this can have spectacular consequences on densely interconnected filament networks, similar to the ones found in cells. Our results demonstrate how the physical context affects the biochemical action of proteins acting on actin filaments, and how this can regulate their activities.

Contact : Guillaume Rommet-Lemonne, team "Regulatiion of Actin Assembly Dynamics".

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