TY - JOUR
T1 - Directional allosteric regulation of protein filament length
AU - Jermyn, Adam S.
AU - Cao, Wenxiang
AU - Elam, W. Austin
AU - De La Cruz, Enrique M.
AU - Lin, Milo M.
N1 - Funding Information:
This work was supported by National Institutes of Health R01 Grant No. GM097348 (awarded to E.M.D.L.C.) and by a Heising-Simons Foundation and Welch Foundation award (Grant No. I-1958-20180324) to M.M.L. This research was supported in part by the National Science Foundation under Grant No. NSF PHY-1748958 and by the Gordon and Betty Moore Foundation through Grant No. GBMF7392. We acknowledge support from the Center for Scientific Computing from the CNSI, MRL: an NSF MRSEC (Grant No. DMR-1720256). A.S.J. acknowledges support from a Marshall Scholarship, Goldwater Scholarship, the Gordon and Betty Moore Fundation (Grant No. GBMF7392), the National Science Foundation (NSF Grant No. PHY-1748958), the Flatiron Institute of the Simons Foundation, and the UT Southwestern Green Endowment for financial support. The authors also thank the late Tom Tombrello for initiating collaborations between A.S.J. and M.M.L. All authors declare no competing interests, financial or nonfinancial.
Publisher Copyright:
© 2020 American Physical Society.
PY - 2020/3
Y1 - 2020/3
N2 - 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.
AB - 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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U2 - 10.1103/PhysRevE.101.032409
DO - 10.1103/PhysRevE.101.032409
M3 - Article
C2 - 32290018
AN - SCOPUS:85082761984
SN - 2470-0045
VL - 101
JO - Physical Review E
JF - Physical Review E
IS - 3
M1 - 032409
ER -