Oral Presentation 9th General Meeting of the International Proteolysis Society 2015

Residues involved in rate enhancement during intramembrane proteolysis (#18)

M Joanne Lemieux 1 , Cameron C Smithers 1 , Elena Arutyunova 1 , Valentina Corradi 2 , Pankaj Panwar 1 3 , Adam C Espiritu 1 , D. Peter Tieleman 2
  1. University of Alberta, Edmonton, ALBERTA, Canada
  2. Department of Biological Sciences and Centre for Molecular Simulation, University of Calgary, Calgary Alberta, Canada
  3. Department of Biochemistry, University of British Columbia, Vancouver, Canada

Proteolysis requires charge stabilization of an oxyanion intermediate for catalytic rate enhancement. Although this is a well-studied concept with soluble proteases, little is known regarding the kinetics of substrate cleavage and charge stabilization by intramembrane proteases. Rhomboids are ubiquitous intramembrane serine proteases involved in various signalling pathways. Crystal structures of E. coli rhomboid proteases revealed a catalytic serine-histidine dyad buried within a helical bundle. High-resolution structures of the E. coli protease rhomboid, GlpG, with mechanism-based inhibitors and peptide-inhibitor complexes disclosed residues involved in the catalytic mechanism; however, for AarA rhomboid, for which the physiologic substrate psTatA is known, limited research has been conducted. A homology model of AarA was used to identify the residues that are important for catalysis. With kinetic analysis of psTatA cleavage by AarA, we provide a direct and quantitative evaluation of the role of several residues important for hydrolytic efficiency and oxyanion stabilization during intramembrane proteolysis.