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bioRxiv · 10.1101/2020.09.30.320812

The genotype-phenotype landscape of an allosteric protein

Tack, D. S.·Tonner, P. D.·Pressman, A.·Olson, N. D.·Levy, S. F.·Romantseva, E. F.·Alperovich, N.·Vasilyeva, O.·Ross, D.
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Abstract

Allostery is a fundamental biophysical mechanism that underlies cellular sensing, signaling, and metabolism. Yet a quantitative understanding of allosteric genotype-phenotype relationships remains elusive. Here we report the large-scale measurement of the genotype-phenotype landscape for an allosteric protein: the lac repressor from Escherichia coli, LacI. Using a method that combines long-read and short-read DNA sequencing, we quantitatively measure the dose-response curves for nearly 105 variants of the LacI genetic sensor. The resulting data provide a quantitative map of the effect of amino acid substitutions on LacI allostery and reveal systematic sequence-structure-function relationships. We find that in many cases, allosteric phenotypes can be quantitatively predicted with additive or neural-network models, but unpredictable changes also occur. For example, we were surprised to discover a new band-stop phenotype that challenges conventional models of allostery and that emerges from combinations of nearly silent amino acid substitutions.

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Tack, D. S., Tonner, P. D., Pressman, A., Olson, N. D., Levy, S. F., Romantseva, E. F., Alperovich, N., Vasilyeva, O., Ross, D.. 2020-09-30. The genotype-phenotype landscape of an allosteric protein. https://doi.org/10.1101/2020.09.30.320812

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