Year: 2021
Type: article
Abstract: Epistasis is a major determinant in the emergence of novel protein function. In allosteric proteins, direct interactions between inducer-binding mutations propagate through the allosteric network, manifesting as epistasis at the level of biological function. Elucidating this relationship between local interactions and their global effects is essential to understanding evolution of allosteric proteins. We integrate computational design, structural and biophysical analysis to characterize the emergence of novel inducer specificity in an allosteric transcription factor. Adaptive landscapes of different inducers of the designed mutant show that a few strong epistatic interactions constrain the number of viable sequence pathways, revealing ridges in the fitness landscape leading to new specificity. The structure of the designed mutant shows that a striking change in inducer orientation still retains allosteric function. Comparing biophysical and functional properties suggests a nonlinear relationship between inducer binding affinity and allostery. Our results highlight the functional and evolutionary complexity of allosteric proteins.
Source: Nature Communications
Institution: University of Wisconsin–Madison
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $5,560
Funders: National Science Foundation, U.S. Department of Defense, U.S. Department of Energy, Wisconsin Alumni Research Foundation, Michigan Economic Development Corporation, National Institutes of Health, Office of Science, Michigan Technology Tri-Corridor, National Institute of General Medical Sciences, Army Research Office, Argonne National Laboratory
Awards: G102163711, G107546177, G1313983767, G1505794299, G1664757510, G1947107004, G2101401529, G2287611682, G262962599, G2887060908, G2896567508, G3075337988, G3141641755, G3329398301, G340565428, G416541740, G4773269573, G498139845, G5106849484, G513797252, G5607048534, G5906309288, G6101244626, G641989812, Graduate Training in Molecular Biosciences, G6848031779, G6918803902, G7147508703, G7368700025, G7452299184, G8362364538, RADICAL REDESIGN OF AN ALLOSTERIC BIOSENSOR TO RESPOND TO NEW LIGANDS, G8764064047, G969889393, G993149817
OpenAlex ID: W3199546810