PT  - JOURNAL ARTICLE
AU  - Tack, Drew S.
AU  - Tonner, Peter D.
AU  - Pressman, Abe
AU  - Olson, Nathanael D.
AU  - Levy, Sasha F.
AU  - Romantseva, Eugenia F.
AU  - Alperovich, Nina
AU  - Vasilyeva, Olga
AU  - Ross, David
TI  - The genotype-phenotype landscape of an allosteric protein
AID  - 10.1101/2020.09.30.320812
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.09.30.320812
4099  - http://biorxiv.org/content/early/2020/09/30/2020.09.30.320812.short
4100  - http://biorxiv.org/content/early/2020/09/30/2020.09.30.320812.full
AB  - 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.Competing Interest StatementThe authors have declared no competing interest.