PUBLICATION
Structural and mechanistic insights into secretagogin-mediated exocytosis
- Authors
- Qin, J., Liu, Q., Liu, Z., Pan, Y.Z., Sifuentes-Dominguez, L., Stepien, K.P., Wang, Y., Tu, Y., Tan, S., Wang, Y., Sun, Q., Mo, X., Rizo, J., Burstein, E., Jia, D.
- ID
- ZDB-PUB-200403-29
- Date
- 2020
- Source
- Proceedings of the National Academy of Sciences of the United States of America 117: 6559-6570 (Journal)
- Registered Authors
- Mo, Xianming
- Keywords
- SNAP-25, SNARE, neurological disorder, neuronal development, regulated exocytosis
- MeSH Terms
-
- Animals
- Binding Sites
- Brain/growth & development
- Brain/metabolism
- Calcium/metabolism
- Cell Line
- Cell Membrane/metabolism
- Exocytosis*
- Gene Expression Regulation, Developmental
- Humans
- Mutation
- Protein Binding
- Protein Conformation
- Secretagogins/chemistry*
- Secretagogins/genetics
- Secretagogins/metabolism*
- Synaptosomal-Associated Protein 25/genetics
- Synaptosomal-Associated Protein 25/metabolism
- Zebrafish
- PubMed
- 32156735 Full text @ Proc. Natl. Acad. Sci. USA
Citation
Qin, J., Liu, Q., Liu, Z., Pan, Y.Z., Sifuentes-Dominguez, L., Stepien, K.P., Wang, Y., Tu, Y., Tan, S., Wang, Y., Sun, Q., Mo, X., Rizo, J., Burstein, E., Jia, D. (2020) Structural and mechanistic insights into secretagogin-mediated exocytosis. Proceedings of the National Academy of Sciences of the United States of America. 117:6559-6570.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping