Structural and mechanistic insights into secretagogin-mediated exocytosis.

Proceedings of the National Academy of Sciences of the United States of America
Jiao QinDa Jia

Abstract

Secretagogin (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.

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Citations

Jul 28, 2020·Journal of Clinical Medicine·Carola DeischingerAlexandra Kautzky-Willer
Apr 6, 2021·Frontiers in Cell and Developmental Biology·Quirino Attilio VassalliAnnamaria Locascio
May 15, 2021·Nature Structural & Molecular Biology·Lvqin ZhengDa Jia
Sep 1, 2021·Proceedings of the National Academy of Sciences of the United States of America·Xin YongDa Jia

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