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bioRxiv · 10.1101/2021.08.20.457087

Small disulfide loops in peptide hormones mediate self-aggregation and secretory granule sorting

Reck, J. R.·Beuret, N.·Demirci, E.·Prescianotto-Baschong, C.·Spiess, M.
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Abstract

Unlike constitutively secreted proteins, peptide hormones are stored in densely packed secretory granules, before regulated release upon stimulation. Secretory granules are formed at the trans-Golgi network (TGN) by self-aggregation of prohormones as functional amyloids. The nonapeptide hormone vasopressin, which forms a small disulfide loop, was shown to be responsible for granule formation of its precursor in the TGN as well as for toxic fibrillar aggregation of unfolded mutants in the endoplasmic reticulum (ER). Several other hormone precursors also contain similar small disulfide loops suggesting their function as a general device to mediate aggregation for granule biogenesis. To test this hypothesis, we studied the capacity of small disulfide loops of different hormone precursors to mediate aggregation in the ER and the TGN. They indeed induced ER aggregation although to different extents in Neuro-2a and COS-1 cells. Fused to a constitutively secreted reporter protein, they also promoted sorting into secretory granules, enhanced stimulated secretion, and increased Lubrol insolubility in AtT20 cells. These results support the hypothesis that small disulfide loops act as novel signals for secretory granule biogenesis and sorting by self-aggregation.

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Reck, J. R., Beuret, N., Demirci, E., Prescianotto-Baschong, C., Spiess, M.. 2021-08-20. Small disulfide loops in peptide hormones mediate self-aggregation and secretory granule sorting. https://doi.org/10.1101/2021.08.20.457087

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