|ZFIN ID: ZDB-PUB-200403-29|
Structural and mechanistic insights into secretagogin-mediated exocytosis
Qin, J., Liu, Q., Liu, Z., Pan, Y.Z., Sifuentes-Dominguez, L., Stepien, K.P., Wang, Y., Tu, Y., Tan, S., Wang, Y., Sun, Q., Mo, X., Rizo, J., Burstein, E., Jia, D.
|Source:||Proceedings of the National Academy of Sciences of the United States of America 117: 6559-6570 (Journal)|
|Registered Authors:||Mo, Xianming|
|Keywords:||SNAP-25, SNARE, neurological disorder, neuronal development, regulated exocytosis|
|PubMed:||32156735 Full text @ Proc. Natl. Acad. Sci. USA|
Qin, J., Liu, Q., Liu, Z., Pan, Y.Z., Sifuentes-Dominguez, L., Stepien, K.P., Wang, Y., Tu, Y., Tan, S., Wang, Y., Sun, Q., Mo, X., Rizo, J., Burstein, E., Jia, D. (2020) Structural and mechanistic insights into secretagogin-mediated exocytosis. Proceedings of the National Academy of Sciences of the United States of America. 117:6559-6570.
ABSTRACTSecretagogin (SCGN) is a hexa-EF-hand protein that is highly expressed in the pancreas, brain, and gastrointestinal tract. SCGN is known to modulate regulated exocytosis in multiple cell lines and tissues; however, its exact functions and underlying mechanisms remain unclear. Here, we report that SCGN interacts with the plasma membrane SNARE SNAP-25, but not the assembled SNARE complex, in a Ca2+-dependent manner. The crystal structure of SCGN in complex with a SNAP-25 fragment reveals that SNAP-25 adopts a helical structure and binds to EF-hands 5 and 6 of SCGN. SCGN strongly inhibits SNARE-mediated vesicle fusion in vitro by binding to SNAP-25. SCGN promotes the plasma membrane localization of SNAP-25, but not Syntaxin-1a, in SCGN-expressing cells. Finally, SCGN controls neuronal growth and brain development in zebrafish, likely via interacting with SNAP-25 or its close homolog, SNAP-23. Our results thus provide insights into the regulation of SNAREs and suggest that aberrant synapse functions underlie multiple neurological disorders caused by SCGN deficiency.