Signal-mediated sorting to the regulated pathway of protein secretion

The existence of specific sorting signals which direct regulated secretory proteins to secretory granules (SGs) was hypothesized two decades ago and s ince then has been addressed in numerous studies. The discovery that aggreg ation of regulated secretory proteins is involved in their sorting to SGs q uestioned the existence of specific sorting signals. In this short review w e summarize the identification of a specific sorting signal for chromograni n B (CgB), a regulated secretory protein which undergoes Ca2+/pH-dependent aggregation. This signal is represented by the N-terminal disulfide-bonded loop of CgB encoded by exon 3 and is necessary to direct CgB to SGs. Its es sential role was revealed only by the expression of a loopless deletion mut ant in the absence of endogenous protein synthesis to preclude aggregative sorting of the former with the latter. The signal is also sufficient to dir ect a reporter protein to SGs, but only its multiple presence on the report er leads to high sorting efficiency. Importantly, the identified signal fun ctions at the level of the TGN by binding to membrane components that give rise to SGs. Furthermore, these studies lead to further insights into the m echanism of sorting. First, conclusive evidence is provided that regulated secretory proteins lacking a specific signal, can be sorted via coaggregati on with proteins containing a specific sorting signal. Second, the data sup port an additional function of aggregation in the TGN which is multimerizat ion of sorting signals per sorting unit leading to highly efficient sorting to SGs.