Structural Studies of Aminopeptidase P

The plasma membrane of many cell types contains a cohort of peptidases that serve to modulate the activity of circulating regulatory peptides. Many of these are zinc metallopeptidases and these enzymes are particularly abundant in the brush border membranes of renal and intestinal microvilli. Some of them such as neprilysin (NEP; EC 3.4.24.11) and aminopeptidase N (AP-N; EC 3.4.11.2) also exist as cluster differentiation antigens (CD10 and CD 13 respectively) on the surface of leukocytes and may play a role in regulation of the immune system1. Both NEP and AP-N also have roles in the metabolism of certain cardiovascular and neuropeptides, e.g. natriuretic peptides2 and enkephalins3. NEP and AP-N are type ll integral membrane proteins and possess the typical HExxH zincin motif4 characteristic of many zinc peptidases. Recently, we have focused on another brush border zinc peptidase, aminopeptidase P (AP-P; X-Pro aminopeptidase; EC 3.4.11.9) which we showed to be unusual among the membrane peptidases in being anchored to the membrane by a glycosylphosphatidylinositol (GPI) moiety5. AP-P also shows a number of other atypical features which led us to attempt the molecular cloning of the pig kidney enzyme.