TY - JOUR
T1 - Structural and mechanistic insights into secretagogin-mediated exocytosis
AU - Qin, Jiao
AU - Liu, Qi
AU - Liu, Zhe
AU - Pan, Yun Zu
AU - Sifuentes-Dominguez, Luis
AU - Stepien, Karolina P.
AU - Wang, Yan
AU - Tu, Yingfeng
AU - Tan, Shuai
AU - Wang, Yuan
AU - Sun, Qingxiang
AU - Mo, Xianming
AU - Rizo, Josep
AU - Burstein, Ezra
AU - Jia, Da
N1 - Funding Information:
ACKNOWLEDGMENTS. We thank members of our laboratory for helpful discussions, and Mr. Chengxin Weng for help with making figures. This research is supported by Natural Science Foundation of China Grants 91854121, 31871429, and 31671477; National Key Research and Development Program of China (Grants 2018YFC1005004, 2015CB942800); Sichuan Science and Technology Program (Grant 2018RZ0128); Welch Foundation Grant I-1304 (to J.R.); and NIH Grant NS097333 (to J.R.).
Publisher Copyright:
© 2020 National Academy of Sciences. All rights reserved.
PY - 2020/3/24
Y1 - 2020/3/24
N2 - 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.
AB - 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.
KW - Neurological disorder
KW - Neuronal development
KW - Regulated exocytosis
KW - SNAP-25
KW - SNARE
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U2 - 10.1073/pnas.1919698117
DO - 10.1073/pnas.1919698117
M3 - Article
C2 - 32156735
AN - SCOPUS:85082339670
SN - 0027-8424
VL - 117
SP - 6559
EP - 6570
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 12
ER -