Ligand-specific changes in conformational flexibility mediate long-range allostery in the lac repressor

Anum Glasgow (), Helen T. Hobbs, Zion R. Perry, Malcolm L. Wells, Susan Marqusee and Tanja Kortemme
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Anum Glasgow: University of California
Helen T. Hobbs: University of California, Berkeley
Zion R. Perry: Yale University
Malcolm L. Wells: Columbia University
Susan Marqusee: University of California, Berkeley
Tanja Kortemme: University of California

Nature Communications, 2023, vol. 14, issue 1, 1-15

Abstract: Abstract Biological regulation ubiquitously depends on protein allostery, but the regulatory mechanisms are incompletely understood, especially in proteins that undergo ligand-induced allostery with few structural changes. Here we used hydrogen-deuterium exchange with mass spectrometry (HDX/MS) to map allosteric effects in a paradigm ligand-responsive transcription factor, the lac repressor (LacI), in different functional states (apo, or bound to inducer, anti-inducer, and/or DNA). Although X-ray crystal structures of the LacI core domain in these states are nearly indistinguishable, HDX/MS experiments reveal widespread differences in flexibility. We integrate these results with modeling of protein-ligand-solvent interactions to propose a revised model for allostery in LacI, where ligand binding allosterically shifts the conformational ensemble as a result of distinct changes in the rigidity of secondary structures in the different states. Our model provides a mechanistic basis for the altered function of distal mutations. More generally, our approach provides a platform for characterizing and engineering protein allostery.

Date: 2023
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DOI: 10.1038/s41467-023-36798-1

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