Multiple stable conformations account for reversible concentration-dependent oligomerization and autoinhibition of a metamorphic metallopeptidase

Abstract

© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim. Molecular plasticity controls enzymatic activity: the native fold of a protein in a given environment is normally unique and at a global free-energy minimum. Some proteins, however, spontaneously undergo substantial fold switching to reversibly transit between defined conformers, the >metamorphic> proteins. Here, we present a minimal metamorphic, selective, and specific caseinolytic metallopeptidase, selecase, which reversibly transits between several different states of defined three-dimensional structure, which are associated with loss of enzymatic activity due to autoinhibition. The latter is triggered by sequestering the competent conformation in incompetent but structured dimers, tetramers, and octamers. This system, which is compatible with a discrete multifunnel energy landscape, affords a switch that provides a reversible mechanism of control of catalytic activity unique in nature. Shape shifting: A minimal metamorphic, selective, and specific caseinolytic metallopeptidase, selecase, reversibly transits between several different states of defined three-dimensional structure (monomer and tetramer represented in picture). The competent conformation is sequestered in incompetent but structured dimers, tetramers, and octamers, which are associated with loss of enzymatic activity due to autoinhibition.