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Botulinum Toxins A and E Inflict Dynamic Destabilization on t-SNARE to Impair SNARE Assembly and Membrane Fusion.

Authors
  • Khounlo, Ryan1
  • Kim, Jaewook1
  • Yin, Linxiang1
  • Shin, Yeon-Kyun2
  • 1 Roy J. Carver Department of Biochemistry, Biophysics & Molecular Biology, Iowa State University, Ames, IA 50011, USA.
  • 2 Roy J. Carver Department of Biochemistry, Biophysics & Molecular Biology, Iowa State University, Ames, IA 50011, USA. Electronic address: [email protected]
Type
Published Article
Journal
Structure
Publisher
Elsevier
Publication Date
Nov 07, 2017
Volume
25
Issue
11
Identifiers
DOI: 10.1016/j.str.2017.09.004
PMID: 29033286
Source
Medline
Keywords
License
Unknown

Abstract

Botulinum toxins (BoNTs) A and E block neurotransmitter release by specifically cleaving the C- terminal ends of SNAP-25, a plasma membrane SNARE protein. Here, we find that SNAP-25A and E, the cleavage products of BoNT A and E, respectively, terminate membrane fusion via completely different mechanisms. Combined studies of single-molecule FRET and single-vesicle fusion assays reveal that SNAP-25E is incapable of supporting SNARE pairing and thus, vesicle docking. In contrast, SNAP-25A facilitates robust SNARE pairing and vesicle docking with somewhat reduced SNARE zippering, which leads to severe impairment of fusion pore opening. The electron paramagnetic resonance results show that the discrepancy between SNAP-25A and E might stem from the extent of the dynamic destabilization of the t-SNARE core at the N-terminal half, which plays a pivotal role in nucleating SNARE complex formation. Thus, the results provide insights into the structure/dynamics-based mechanism by which BoNT A and E impair membrane fusion.

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