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Structural and mechanistic insights into secretagogin-mediated exocytosis.


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.

SUBMITTER: Qin J 

PROVIDER: S-EPMC7104245 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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Structural and mechanistic insights into secretagogin-mediated exocytosis.

Qin Jiao J   Liu Qi Q   Liu Zhe Z   Pan Yun-Zu YZ   Sifuentes-Dominguez Luis L   Stepien Karolina P KP   Wang Yan Y   Tu Yingfeng Y   Tan Shuai S   Wang Yuan Y   Sun Qingxiang Q   Mo Xianming X   Rizo Josep J   Burstein Ezra E   Jia Da D  

Proceedings of the National Academy of Sciences of the United States of America 20200310 12


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 Ca<sup>2+</sup>-dependent manner. The crystal structure of SCGN in complex with a SNAP-25 fragment reveal  ...[more]

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