Shape-shifting proteins and the subtlety in their form and function.

Shape-shifting proteins include intrinsically disordered proteins (IDPs) and fold-switching, or metamorphic proteins. They make up a significant fraction of the "dark proteome" in the protein universe. In this essay, we highlight some often misconceived or underappreciated features of shape-shifting proteins: First, the subtlety of the structure of IDPs; second, the relationship between intrinsic disorder and allostery, third, the possibility of discerning IDP conformational preferences based on energy landscape theory, and fourth, the contributions of disordered regions to fold switching in metamorphic proteins. Lastly, we highlight emerging evidence that fold-switching/metamorphic proteins may contribute to phenotypic plasticity and adaptive evolution by acting as evolutionary capacitors.