Two activation states of the prohormone convertase PC1 in the secretory pathway.
PC1, a neuroendocrine member of the prohormone convertase family of serine proteinases, is implicated in the processing of proproteins in the secretory pathway. PC1 is synthesized as a zymogen and cleaves not only its own profragment in the endoplasmic reticulum, but a subset of protein substrates in the Golgi apparatus and in the Golgi-distal compartments 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 PC1 activity against certain substrates in the endoplasmic reticulum and Golgi apparatus, and its removal, which occurs naturally in secretory granules, may explain the observed granule-specific processing of certain proproteins. These results also demonstrate that PC1 is present in a partially active state prior to the secretory granules where it is processed to a maximally active state.
Jutras
I
I
Laboratory of Molecular Biochemistry of Hypertension, Clinical Research Institute of Montreal (IRCM), Montreal, Quebec, Canada H2W 1R7.
Seidah
N G
NG
Reudelhuber
T L
TL
Brechler
V
V
D000595:Amino Acid Sequence; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000378:metabolism*; D016466:CHO Cells; D002460:Cell Line; D006224:Cricetinae; D004789:Enzyme Activation; D004792:Enzyme Precursors / Q000378:metabolism; D006801:Humans; D008969:Molecular Sequence Data; D045664:Proprotein Convertase 1; D043484:Proprotein Convertases; D011499:Protein Processing, Post-Translational; D051381:Rats; D012083:Renin / Q000378:metabolism; D017386:Sequence Homology, Amino Acid
D004792:Enzyme Precursors; D043484:Proprotein Convertases; C473656:Pcsk1 protein, mouse; D045664:Proprotein Convertase 1; D016282:Aspartic Acid Endopeptidases; D012083:Renin