RT Journal Article
SR Electronic
T1 Small disulfide loops in peptide hormones mediate self-aggregation and secretory granule sorting
JF Life Science Alliance
JO Life Sci. Alliance
FD Life Science Alliance LLC
SP e202101279
DO 10.26508/lsa.202101279
VO 5
IS 5
A1 Jennifer Reck
A1 Nicole Beuret
A1 Erhan Demirci
A1 Cristina Prescianotto-Baschong
A1 Martin Spiess
YR 2022
UL https://www.life-science-alliance.org/content/5/5/e202101279.abstract
AB Unlike constitutively secreted proteins, peptide hormones are stored in densely packed secretory granules, before regulated release upon stimulation. Secretory granules are formed at the 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 ER. Several other hormone precursors also contain similar small disulfide loops suggesting their function as a general device to mediate aggregation for granule sorting. 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 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 sorting into secretory granules by self-aggregation.