Allostery: How Proteins Transmit Information
Allostery is one of the fundamental mechanisms by which proteins regulate biological processes. In an allosteric protein, a perturbation at one site—such as ligand binding—changes activity at a distant functional site. This long-range communication allows proteins to act as molecular switches that control gene expression, metabolism, and cellular signaling.
Despite decades of study, the rules that govern allosteric signaling remain difficult to predict. Allosteric effects are rarely confined to a single structural pathway connecting input and output sites. Instead, signaling often emerges from distributed networks of residues that collectively shape the energetic landscape of the protein. Mutations far from an active site can disrupt signaling, restore lost function, or even create new regulatory behaviors.
Our laboratory studies allostery by systematically perturbing protein sequences and measuring the functional consequences at scale. Using pooled mutational libraries and high-throughput functional assays, we generate dense sequence–function landscapes that reveal how signaling networks are encoded in protein sequence. By comparing these landscapes across multiple protein architectures, we aim to uncover general principles that explain how proteins transmit information—and how those signaling pathways can be rewired through evolution or engineering.
Allosteric Transcription Factors
Allosteric transcription factors (aTFs) regulate gene expression by coupling ligand binding to DNA binding. When a small molecule binds to the transcription factor, it alters the protein’s conformation and changes its affinity for operator DNA, thereby switching
transcription on or off. Because transcriptional output can be directly measured in cells, these proteins provide an ideal system for dissecting the thermodynamic logic of allosteric switching.
Our laboratory uses high-throughput mutational approaches to map how sequence changes influence the regulatory behavior of these proteins. By measuring the activity of thousands of variants in parallel, we can identify mutations that disrupt signaling,
mutations that restore function, and networks of residues that transmit allosteric information across the protein.
These experiments reveal that allosteric regulation is often surprisingly plastic. Mutations that break signaling can frequently be rescued by compensatory mutations at distant sites, suggesting that proteins can use multiple alternative pathways to transmit regulatory signals. Beyond understanding natural regulation, we use these insights to engineer transcription factors with new sensing capabilities, enabling the creation of programmable biosensors and regulatory circuits for synthetic biology.