FIGURE 1. The evolution of interacting proteins and allostery by single mutations.

Two separate proteins in a cell are shown (left). Most cellular proteins are present at nanomolar-to-micromolar concentrations. A single random mutation in either protein is highly unlikely to result in binding or allostery. Interaction between these two proteins becomes probable when they are colocalized. Colocalization (second column) can occur by several mechanisms: by a gene fusion that results in both proteins being part of the same polypeptide chain, by concentration in a microcompartment, by association with the plasma membrane, or by binding to DNA. This process boosts the effective concentration of the proteins with respect to each other. Now, a single point mutation can lower the dissociation constant enough for a selectable change in function to occur. Further single mutations that increase the affinity of the two domains for each other, or that introduce allostery, can be selected for, resulting in tight interactions between these sites or allosteric coupling. Additional single genetic events such as gene fission or loop shortening can result in a strongly interacting heterodimer or an oligomeric homodimer.