The genotype-phenotype landscape of an allosteric protein

Published

December 16, 2021

Author(s)

Drew S. Tack, Peter Tonner, Abe Pressman, Nathanael Olson, Eugenia Romantseva, Nina Alperovich, Olga Vasilyeva, David Ross, Sasha F. Levy

Abstract

Allostery is a fundamental biophysical mechanism where the activity of a biomolecule is regulated by the binding of a ligand. Despite playing a central role in many biological processes, a quantitative understanding of allostery is lacking. To systematically and quantitatively examine the genotype- phenotype relationships for an allosteric transcription factor, we measured the in vivo dose- response curves of over 60,000 randomly mutated variants of the lac repressor, LacI. The resulting data and a deep neural network model provide a comprehensive map of the impact of mutations on the dose- response curve, and hint at structure-based design rules underpinning the function of allosteric proteins. Further, we analyzed mutations associated with significant qualitative changes to the LacI phenotype: inverted and band-stop dose-response curves. The results suggest that these two phenotypes are biophysically distinct and that each can result from a diverse set of mutations.

Citation

Molecular Systems Biology

Volume

17

Pub Type

Journals

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DOI Link

Keywords

allostery, large-scale, deep sequencing, allosteric

Citation

Tack, D. , Tonner, P. , Pressman, A. , Olson, N. , Romantseva, E. , Alperovich, N. , Vasilyeva, O. , Ross, D. and Levy, S. (2021), The genotype-phenotype landscape of an allosteric protein, Molecular Systems Biology, [online], https://doi.org/10.15252/msb.202010179 (Accessed May 16, 2026)

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