Enhancing the activity of a protein by stereospecific unfolding: conformational life cycle of insulin and its evolutionary origins.

ABSTRACT: A central tenet of molecular biology holds that the function of a protein is mediated by its structure. An inactive ground-state conformation may nonetheless be enjoined by the interplay of competing biological constraints. A model is provided by insulin, well characterized at atomic resolution by x-ray crystallography. Here, we demonstrate that the activity of the hormone is enhanced by stereospecific unfolding of a conserved structural element. A bifunctional beta-strand mediates both self-assembly (within beta-cell storage vesicles) and receptor binding (in the bloodstream). This strand is anchored by an invariant side chain (Phe(B24)); its substitution by Ala leads to an unstable but native-like analog of low activity. Substitution by d-Ala is equally destabilizing, and yet the protein

SUBMITTER: Hua QX 

PROVIDER: S-EPMC2682906 | biostudies-literature | 2009 May

REPOSITORIES: biostudies-literature