Focal adhesions as mechanosensors: a physical mechanism - PubMed (original) (raw)

Focal adhesions as mechanosensors: a physical mechanism

Tom Shemesh et al. Proc Natl Acad Sci U S A. 2005.

Abstract

Focal adhesions (FA) are large, multiprotein complexes that provide a mechanical link between the cytoskeletal contractile machinery and the extracellular matrix. FA exhibit mechanosensitive properties; they self-assemble and elongate upon application of pulling forces and dissociate when these forces are decreased. We propose a thermodynamic model for the mechanosensitivity of FA, according to which a molecular aggregate, subjected to pulling forces, tends to grow in the direction of force application by incorporating additional molecules. We demonstrate that this principle is consistent with the phenomenology of FA dynamics by considering a one-dimensional protein aggregate subjected to pulling forces and anchored to the substrate. Depending on the force level, force distribution along the aggregate, and the character of its anchoring to the substrate, the aggregate is predicted to exhibit distinct modes of assembly that are largely consistent with the experimentally observed FA behavior. We define here specific conditions that can lead to the different regimes of FA assembly, including growth, steady state, and disassembly.

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Figures

Fig. 1.

Fig. 1.

Schematic representation of self-assembly upon pulling force. (a) The protein aggregate and the free proteins in the surrounding medium. (b) Application of the pulling force results in the aggregate stretching and the related accumulation of the elastic stresses within the aggregate. (c) Insertion of new proteins into the aggregate results in stress relaxation.

Fig. 2.

Fig. 2.

A 1D aggregate subject to pulling forces f and anchored to substrate, showing an illustration of the model. The points of force application and the points of anchoring are distributed along the aggregate surface, each with its own density.

Fig. 3.

Fig. 3.

Four regimes of self-assembly determined by the parameter χ = (_f_·_l_0)/(Δμ0). The curves represent the total protein flux, J(arbitrary units), to the aggregate as a function of the aggregate length, L(arbitrary units). (a) Atχ < 1, and χ < χ*, the flux is negative, meaning that the aggregate undergoes disintegration. (_b_) At χ > 1, and χ > χ*, the flux is positive, meaning that the aggregate undergoes unlimited growth. (c) At χ < 1 but χ > χ*, the flux is negative until the aggregate reaches a certain length where the flux changes sign and starts increasing with the aggregate length. This regime corresponds to unlimited growth after overcome of a critical length. (d) At χ > 1 and χ <χ*, the flux remains positive until the aggregate reaches a critical length. For length larger than the critical values, the flux is negative. This state is the steady-state regime, where the critical length corresponds to the stable steady-state length of the aggregate.

Fig. 4.

Fig. 4.

Phase diagram of the system representing the different regimes of the aggregate assembly–disassembly corresponding to different ranges of the system parameters, which are the density of the points of force application along the aggregate length ϕ_f_, the density of the points of the aggregate anchoring to the substrate ϕ_A_, and the dimensionless parameter χ = (_f_·_l_0)/(Δμ0), characterizing the ratio between the molecular energy provided by an elementary pulling force, _f_·_l_0, and the difference of the protein standard chemical potentials in the aggregated and free states, Δμ0.

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