Structural and mechanistic insights into secretagogin-mediated exocytosis
Structural and mechanistic insights into secretagogin-mediated exocytosis
复制标题
促泌素介导的胞吐作用的结构和机制见解
DOI：
10.1073/pnas.1919698117
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发表时间：
2020-03-24
影响因子：
11.1
通讯作者：
Jia, Da
中科院分区：
文献类型：
--
作者：
Qin, Jiao;Liu, Qi;Jia, Da
Significance The SNARE complex plays a central role in exocytosis. Secretagogin (SCGN) modulates exocytosis in multiple cell lines and tissues, and its deficiency has been linked with several neurodevelopmental and neurodegenerative diseases. To precisely define the mechanisms by which SCGN regulates exocytosis, we utilized an array of approaches, including X-ray crystallography, cell biology, and a zebrafish model. We show that SNAP-25 binds SCGN, in a conformation incompatible with assembly with other SNARE proteins. SCGN promotes proper cellular localization of SNAP-25 in multiple SCGN-expressing cell lines. Furthermore, the interaction between SCGN and SNAP-25 (and/or SNAP-23) is critical for neuronal growth and brain development in zebrafish. Altogether, our results highlight the importance of precise regulation of SNARE functions for human development and diseases. 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.
