Structural and mechanistic insights into secretagogin-mediated exocytosis

Jiao Qin, Qi Liu, Zhe Liu, Yun Zu Pan, Luis Sifuentes-Dominguez, Karolina P. Stepien, Yan Wang, Yingfeng Tu, Shuai Tan, Yuan Wang, Qingxiang Sun, Xianming Mo, Josep Rizo, Ezra Burstein, Da Jia

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)6559-6570
Number of pages12
JournalProceedings of the National Academy of Sciences of the United States of America
Volume117
Issue number12
DOIs
StatePublished - Mar 24 2020

Keywords

  • Neurological disorder
  • Neuronal development
  • Regulated exocytosis
  • SNAP-25
  • SNARE

ASJC Scopus subject areas

  • General

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