Directional allosteric regulation of protein filament length

Adam S. Jermyn, Wenxiang Cao, W. Austin Elam, Enrique M. De La Cruz, and Milo M. Lin
Phys. Rev. E 101, 032409 – Published 13 March 2020

Abstract

Cofilin and ADF are cytoskeleton remodeling proteins that cooperatively bind and fragment actin filaments. Bound cofilin molecules do not directly interact with each other, indicating that cooperative binding of cofilin is mediated by the actin filament lattice. Cofilactin is therefore a model system for studying allosteric regulation of self-assembly. How cofilin binding changes structural and mechanical properties of actin filaments is well established. Less is known about the interaction energies and the thermodynamics of filament fragmentation, which describes the collective manner in which the cofilin concentration controls mean actin filament length. Here, we provide a general thermodynamic framework for allosteric regulation of self-assembly, and we use the theory to predict the interaction energies of experimental actin filament length distributions over a broad range of cofilin binding densities and for multiple cofilactin variants. We find that bound cofilin induces changes in nearby actin-actin interactions, and that these allosteric effects are propagated along the filament to affect up to four neighboring cofilin-binding sites (i.e., beyond nearest-neighbor allostery). The model also predicts that cofilin differentially stabilizes and destabilizes longitudinal versus lateral actin-actin interactions, and that the magnitude, range, asymmetry, and even the sign of these interaction energies can be altered using different actin and cofilin mutational variants. These results demonstrate that the theoretical framework presented here can provide quantitative thermodynamic information governing cooperative protein binding and filament length regulation, thus revealing nanometer length-scale interactions from micron length-scale “wet-lab” measurements.

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  • Received 28 February 2018
  • Accepted 10 February 2020

DOI:https://doi.org/10.1103/PhysRevE.101.032409

©2020 American Physical Society

Physics Subject Headings (PhySH)

Physics of Living SystemsStatistical Physics & Thermodynamics

Authors & Affiliations

Adam S. Jermyn1,2, Wenxiang Cao3, W. Austin Elam3,*, Enrique M. De La Cruz3, and Milo M. Lin2

  • 1Center for Computational Astrophysics,Flatiron Institute, New York, New York, 10010, USA
  • 2Green Center for Molecular, Computational, and Systems Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA
  • 3Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, Connecticut 06511, USA

  • *Current address: C4 Therapeutics, Cambridge, MA 02142, USA.

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Vol. 101, Iss. 3 — March 2020

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