PROLYL OLIGOPEPTIDASE: A -PROPELLER REGULATES CYTOSOLIC PROTEOLYSIS
Vilmos Fülöp
Laboratory of Molecular Biophysics and Oxford Centre for Molecular Sciences, University of Oxford, South Parks Road, Oxford OX1 3QU, U.K. and Department of Biological Sciences, University of Warwick, Gibbet Hill Road, Coventry CV4 7AL, U.K.
Keywords: prolyl oligopeptidse, proteolysis, /
hydrolases, -propeller, amnesia
Prolyl oligopeptidase is a large cytosolic enzyme that belongs to a new class of serine peptidases [1]. The enzyme catalyses the cleavage of several biologically active peptides such as angiotensins I and II, bradykinin, oxytocin and vascopresin. Prolyl oligopeptidase has recently gained pharmaceutical interest, since specific inhibitors reverse scopolamine-induced amnesia in rats. Its activity in plasma correlates with different stages of depression. The enzyme also has a role in the regulation of blood pressure.
The 1.3 A resolution crystal structure is presented here [2]. The enzyme contains a peptidase domain with an a/b hydrolase fold and its catalytic triad (Ser554, His680, Asp641) is covered by the central tunnel of an unusual b-propeller. This domain makes prolyl oligopeptidase an oligopeptidase by excluding large, structured peptides from the active site. In this way the propeller protects larger peptides and proteins from proteolysis in the cytosol. The structure is also obtained with a transition state inhibitor, which facilitates drug design to treat memory disorders.