Binding of BiP to the processing enzyme lymphoma proprotein convertase prevents aggregation, but slows down maturation

Lymphoma proprotein convertase (LPC) is a subtilisin-like serine protease o f the mammalian proprotein convertase family. It is synthesized as an inact ive precursor protein, and propeptide cleavage occurs via intramolecular cl eavage in the endoplasmic reticulum. In contrast to other convertases like furin and proprotein convertase-1, propeptide cleavage occurs slowly, Also, both a glycosylated and an unglycosylated precursor are detected. Here we demonstrate that the unglycosylated precursor form of LPC is localized in t he cytosol due to the absence of a signal peptide. Using a reducible cross- linker, we found that glycosylated pro-LPC is associated with the molecular chaperone BiP. In addition, we show that pro-LPC is prone to aggregation a nd forms large complexes linked via interchain disulfide bonds. BiP is asso ciated mainly with non-aggregated pro-LPC and pro-LPC dimers and trimers, s uggesting that BiP prevents aggregation. Overexpression of wild-type Dip or a dominant-negative BiP ATPase mutant resulted in reduced processing of pr o-LPC. Taken together, these results suggest that binding of BiP to pro-LPC prevents aggregation, but results in slower maturation.