2 ACTIVATION STATES OF THE PROHORMONE-CONVERTASE-PC1 IN THE SECRETORYPATHWAY

PC1, a neuroendocrine member of the prohormone convertase family of se rine proteinases, is implicated in the processing of proproteins in th e secretory pathway, PC1 is synthesized as a zymogen and cleaves not o nly its own profragment in the endoplasmic reticulum, but a subset of protein substrates in the Gels apparatus and in the Golgi-distal compa rtments of the regulated secretory pathway, Likewise, mouse PC1 (mPC1) has previously been shown to cleave human prorenin in GH4 cells (that contain secretory granules) while being unable to cleave prorenin in cells, such as Chinese hamster ovary (CHO) or BSC-40, which are devoid of secretory granules, In the current study, we show that removal of a C-terminal tail of mPC1 allows the efficient cleavage of prorenin in the constitutive secretory pathway of CHO cells, The C-terminal tail thus appears to act as an inhibitor of PCI activity against certain su bstrates in the endoplasmic reticulum and Golgi apparatus, and its rem oval, which occurs naturally in secretory granules, may explain the ob served granule-specific processing of certain proproteins, These resul ts also demonstrate that PC1 is present in a partially active state pr ior to the secretory granules where it is processed to a maximally act ive state.