UMass Chan Medical School Faculty Publications
Title
Biophysical basis of cellular multi-specificity encoded in a model molecular switch [preprint]
UMMS Affiliation
Program in Molecular Medicine; Department of Biochemistry and Molecular Pharmacology
Publication Date
2021-03-21
Document Type
Article Preprint
Disciplines
Amino Acids, Peptides, and Proteins | Biophysics | Molecular Biology | Systems Biology
Abstract
Molecular switches are central to signal transduction in protein interaction networks. One switch protein can independently regulate distinct cellular processes, but the molecular mechanisms enabling this functional multi-specificity remain unclear. Here we integrate system-scale cellular and biophysical measurements to study how a paradigm switch, the small GTPase Ran/Gsp1, achieves its functional multi-specificity. We make 55 targeted point mutations to individual interactions of Ran/Gsp1 and show through quantitative, systematic genetic and physical interaction mapping that Ran/Gsp1 interface perturbations have widespread cellular consequences that cluster by biological processes but, unexpectedly, not by the targeted interactions. Instead, the cellular consequences of the interface mutations group by their biophysical effects on kinetic parameters of the GTPase switch cycle, and cycle kinetics are allosterically tuned by distal interface mutations. We propose that the functional multi-specificity of Ran/Gsp1 is encoded by a differential sensitivity of biological processes to different kinetic parameters of the Gsp1 switch cycle, and that Gsp1 partners binding to the sites of distal mutations act as allosteric regulators of the switch. Similar mechanisms may underlie biological regulation by other GTPases and biological switches. Finally, our integrative platform to determine the quantitative consequences of cellular perturbations may help explain the effects of disease mutations targeting central switches.
Keywords
Ran, Gsp1, GTPase, molecular switches, systems biology, thermodynamic coupling
Rights and Permissions
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
DOI of Published Version
10.1101/2020.01.04.893909
Source
bioRxiv 2020.01.04.893909; doi: https://doi.org/10.1101/2020.01.04.893909. Link to preprint on bioRxiv.
Journal/Book/Conference Title
bioRxiv
Repository Citation
Perica T, Mathy CJ, Xu J, Jang GM, Zhang Y, Kaake R, Ollikainen N, Braberg H, Swaney DL, Lambright DG, Kelly MJ, Krogan NJ, Kortemme T. (2021). Biophysical basis of cellular multi-specificity encoded in a model molecular switch [preprint]. UMass Chan Medical School Faculty Publications. https://doi.org/10.1101/2020.01.04.893909. Retrieved from https://escholarship.umassmed.edu/faculty_pubs/2017
Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License.
Included in
Amino Acids, Peptides, and Proteins Commons, Biophysics Commons, Molecular Biology Commons, Systems Biology Commons
Comments
This article is a preprint. Preprints are preliminary reports of work that have not been certified by peer review.
The PDF available for download is Version 2 of this preprint. The complete version history of this preprint is available at bioRxiv.