A mechanism for the evolution of allosteric control in proteins

Co-evolution analysis indicates a general architecture for natural proteins in which sparse networks of physically contiguous amino acids underlie basic aspects of structure and function. These networks, termed sectors, are spatially organized such that active sites are linked to many surface sites distributed throughout the protein structure. Here, we propose that sectors represent an evolutionarily conserved ``wiring'' mechanism that effectively functionalizes a large but non-random fraction of the protein surface - that is, perturbation at sector-connected surface positions should preferentially yield coupling to the active site. To test this premise, we conducted a comprehensive ``domain insertion scan,'' and show that sector-connected surface sites are statistically significant locations for the emergence of allosteric control in vivo. This finding suggests practical guidelines for the engineering of new allosteric systems, and permits description of a plausible model for the evolution of intermolecular communication and regulation.