Insight into the complex and dynamic process of activation of matrix metalloproteinases

Matrix metalloproteinases (MMPs) are important hydrolytic enzymes with prof ound physiological and pathological functions in living organisms. MMPs are produced in their inactive zymogenic forms, which are subsequently proteol ytically activated in an elaborate set of events. The propeptide in the zym ogen blocks the active site, with a cysteine side-chain thiolate from this propeptide achieving coordination with the catalytically important zinc ion in the active site. Molecular dynamics simulations, ab initio calculations , and wet chemistry experiments presented herein argue for the critical imp ortance of a protonation event at the coordinated thiolate as a prerequisit e for the departure of the propeptide from the active site. Furthermore, a catalytically important glutamate is shown to coordinate transiently to the active-site zinc ion to "mask" the positive potential of the zinc ion and lower the energy barrier fur dissociation of the protonated cysteine side c hain from the zinc ion. In addition, a subtle conformational change by the propeptide is needed in the course of zymogen activation. These elaborate p rocesses take place in concert in the activation process of MMPs, and the i nsight into these processes presented herein sheds light on a highly regula ted physiological process with profound consequences for eukaryotic organis ms.