Milieu-induced, selective aggregation of regulated secretory proteins in the trans-Golgi network

Both in PC12 and GH4C1 cells, the effect of aggregative milieu was remarkably selective for the granins when compared with the behavior of the bulk of the proteins present in the subcellular fractions studied . Furthermore, aggregative milieu did not affect the release of BiP and PDI, two ERresident proteins which have acidic isoelectric points and are able to bind calcium (Lee, 1987; Macer and Koch, 1988) . This suggests that the low pH-, high calcium-induced aggregation of the granins involves specific structural features of these proteins, which is consistent with the hypothesis that regulated secretory proteins have an inherently higher tendency to aggregate than other types ofsoluble proteins ofthe secretory pathway. The observation that aggregative milieu was effective on granins from the RER, i.e., granins which were not yet posttranslationally modified, indicates that these structural features reside in their polypeptide backbones .