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
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
Figures
Expression
Phenotype
Mutation and Transgenics
Human Disease / Model Data
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping
Errata and Notes