Abstract
In allostery, a signal from one site in a protein is transmitted to a second site to alter its function. Due to its ubiquity in biology and the potential for its exploitation in drug and protein design, the molecular basis of allosteric communication continues to be the subject of intense research. Although allosterically coupled sites are frequently characterized by disorder, how communication between disordered segments occurs remains obscure. Allosteric activation of Escherichia coli BirA dimerization occurs via coupled distant disorder-to-order transitions. In this work, combined structural and computational studies reveal an extensive residue network in BirA. Substitution of several network residues yields large perturbations to allostery. Force distribution analysis reveals that disruptions to the disorder-to-order transitions through amino acid substitution are manifested in shifts in the energy experienced by network residues as well as alterations in packing of an α-helix that plays a critical role in allostery. The combined results reveal a highly distributed allosteric mechanism that is robust to sequence change.