Mechanism of substrate recognition by botulinum neurotoxin serotype A

Sheng Chen, Jung Ja P Kim, Joseph T. Barbieri

Research output: Journal article publicationJournal articleAcademic researchpeer-review

68 Citations (Scopus)

Abstract

Botulinum neurotoxins (BoNTs) are zinc proteases that cleave SNARE proteins to elicit flaccid paralysis by inhibiting neurotransmitter-carrying vesicle fusion to the plasma membrane of peripheral neurons. Unlike other zinc proteases, BoNTs recognize extended regions of SNAP25 for cleavage; however, the molecular basis for this extended substrate recognition is unclear. Here, we define a multistep mechanism for recognition and cleavage of SNAP25 by BoNT/A. SNAP25 initially binds along the belt region of BoNT/A, which aligns the P5 residue to the S5 pocket at the periphery of the active site. Although the exact order of each step of recognition of SNAP25 by BoNT/A at the active site is not clear, the initial binding could subsequently orient the P4′-residue of SNAP25 to form a salt bridge with the S4′-residue, which opens the active site allowing the P1′-residue access to the S1′-pocket. Subsequent hydrophobic interactions between the P3 residue of SNAP25 and the S3 pocket optimize alignment of the scissile bond for cleavage. This explains how the BoNTs recognize and cleave specific coiled SNARE substrates and provides insight into the development of inhibitors to prevent botulism.
Original languageEnglish
Pages (from-to)9621-9627
Number of pages7
JournalJournal of Biological Chemistry
Volume282
Issue number13
DOIs
Publication statusPublished - 30 Mar 2007
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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