Mechanisms for storage of prolactin and growth hormone in secretory granules.

There are three steps in the formation of secretory granules: aggregation of proteins to form the dense cores of granules, accumulation of appropriate membrane proteins necessary for function of the granules, and removal of extraneous membrane and inappropriate proteins by small vesicles. Formation of protein aggregates may be the initial step in this process, which is not well understood. Assays of aggregation of human prolactin and growth hormone in neuroendocrine cells indicate that acidic intracellular compartments are necessary, and Zn2+ and Cu2+ may facilitate aggregation through low affinity binding sites. There is more than one way to make proteins aggregate in solution; precipitates of human prolactin formed in "crowded" conditions most closely resemble what is likely to occur in cells. Understanding the properties of aggregates formed in cells may be important, as there are several examples of granules with different contents that function differently; human R183H-growth hormone, a mutant that causes autosomal dominant isolated growth hormone deficiency, also appears to be an example. Recognition of surface motifs on aggregates of proteins may be important to localize correctly membrane proteins necessary for function, an explanation for the means by which granule content may influence function.