Multiple Stable Conformations Account for Reversible Concentration-Dependent Oligomerization and Autoinhibition of a Metamorphic Metallopeptidase

• Published in: Angewandte Chemie 2014-09, Vol.126 (40), p.10800-10806
• Main Authors: López-Pelegrín, Mar, Cerdà-Costa, Núria, Cintas-Pedrola, Anna, Herranz-Trillo, Fátima, Bernadó, Pau, Peinado, Juan R., Arolas, Joan L., Gomis-Rüth, F. Xavier
• Format: Article
• Language: eng ; ger
• Subjects: Chemistry; Control equipment; Landscapes; Metallopeptidasen; Metamorphe Proteine; Metamorphic; Oligomerization; Plasticity; Proteinfaltung; Proteins; Proteinstrukturen; Switches; Switching; Three dimensional; Transit
• ISSN: 0044-8249; 1521-3757
• DOI: 10.1002/ange.201405727

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. Selecase, eine minimale, metamorphe, selektive und spezifische caseinolytische Metallopeptidase, wechselt reversibel zwischen verschiedenen Zuständen mit definierten dreidimensionalen Strukturen (siehe Bilder von Monomer und Tetramer). Die aktive monomere Konformation geht in inaktive, aber strukturierte Dimere, Tetramere und Octamere über, was eine Erklärung für den Verlust der enzymatischen Aktivität durch Selbstinhibition liefert.