A search for synthetic peptides that inhibit soluble N-ethylmaleimide sensitive-factor attachment receptor-mediated membrane fusion

Chang H. Jung, Yoo Soo Yang, Jun Seob Kim, Jae Il Shin, Yong Su Jin, Jae Y. Shin, Jong H. Lee, Koo M. Chung, Jae S. Hwang, Jung M. Oh, Yeon Kyun Shin, Dae Hyuk Kweon

Research output: Contribution to journalArticle

Abstract

Soluble N-ethylmaleimide sensitive-factor attachment receptor (SNARE) proteins have crucial roles in driving exocytic membrane fusion. Molecular recognition between vesicle-associated (v)-SNARE and target membrane (t)-SNARE leads to the formation of a four-helix bundle, which facilitates the merging of two apposing membranes. Synthetic peptides patterned after the SNARE motifs are predicted to block SNARE complex formation by competing with the parental SNAREs, inhibiting neuronal exocytosis. As an initial attempt to identify the peptide sequences that block SNARE assembly and membrane fusion, we created thirteen 17-residue synthetic peptides derived from the SNARE motifs of v- and t-SNAREs. The effects of these peptides on SNARE-mediated membrane fusion were investigated using an in vitro lipid-mixing assay, in vivo neurotransmitter release and SNARE complex formation assays in PC12 cells. Peptides derived from the N-terminal region of SNARE motifs had significant inhibitory effects on neuroexocytosis, whereas middle- and C-terminal-mimicking peptides did not exhibit much inhibitory function. N-terminal mimicking peptides blocked N-terminal zippering of SNAREs, a rate-limiting step in SNARE-driven membrane fusion. Therefore, the results suggest that the N-terminal regions of SNARE motifs are excellent targets for the development of drugs to block SNARE-mediated membrane fusion and neurotransmitter release.

Original languageEnglish (US)
Pages (from-to)3051-3063
Number of pages13
JournalFEBS Journal
Volume275
Issue number12
DOIs
StatePublished - Jun 1 2008
Externally publishedYes

Keywords

  • Exocytosis
  • Membrane fusion
  • Neurotransmitter release
  • SNARE
  • SNARE-patterned peptide

ASJC Scopus subject areas

  • Biochemistry

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  • Cite this

    Jung, C. H., Yang, Y. S., Kim, J. S., Shin, J. I., Jin, Y. S., Shin, J. Y., Lee, J. H., Chung, K. M., Hwang, J. S., Oh, J. M., Shin, Y. K., & Kweon, D. H. (2008). A search for synthetic peptides that inhibit soluble N-ethylmaleimide sensitive-factor attachment receptor-mediated membrane fusion. FEBS Journal, 275(12), 3051-3063. https://doi.org/10.1111/j.1742-4658.2008.06458.x