Multiple Pocket Recognition of Snap25 by Botulinum Neurotoxin Serotype E.
From: Department of Microbiology and Molecular Genetics, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, USA.
The Journal of biological chemistry
- Publish Date: Aug 2007
- ISSN: 0021-9258
- Volume: 282
- Issue: 35
- Pages: 25540-7
- Medium: Print
- Language: English
- Citation (JAMA): Chen Sheng, Barbieri Joseph T, et al. Multiple Pocket Recognition of Snap25 by Botulinum Neurotoxin Serotype E.. J. Biol. Chem. Aug 2007;282:25540-7
Abstract
Botulinum neurotoxins (BoNTs) are zinc proteases that cleave SNARE proteins to elicit flaccid paralysis by inhibiting the fusion of neurotransmitter-carrying vesicles to the plasma membrane of peripheral neurons. There are seven serotypes of BoNT, termed A-G. The molecular basis for SNAP25 recognition and cleavage by BoNT serotype E is currently unclear. Here we define the multiple pocket recognition of SNAP25 by LC/E. The initial recognition of SNAP25 is mediated by the binding of the B region of SNAP25 to the substrate-binding (B) region of LC/E comprising Leu166, Arg167, Asp127, Ala128, Ser129, and Ala130. The mutations at these residues affected substrate binding and catalysis. Three additional residues participate in scissile bond cleavage of SNAP25 by LC/E. The P3 site residues, Ile178, of SNAP25 interacted with the S3 pocket in LC/E through hydrophobic interactions. The S3 pocket included Ile47, Ile164, and Ile182 and appeared to align the P1’ and P2 residues of SNAP25 with the S1’ and S2 pockets of LC/E. The S1’ pocket of LC/E included three residues, Phe191, Thr159, and Thr208, which contribute hydrophobic and steric interactions with the SNAP25 P1’ residue Ile181. The S2 pocket residue of LC/E, Lys224, binds the P2 residue of SNAP25, Asp179, through ionic interactions. Deletion mapping indicates that main chain interaction(s) of residues 182-186 of SNAP25 contribute to substrate recognition by LC/E. Understanding the mechanism for substrate specificity provides insight for the development of inhibitors against the botulinum neurotoxins.
Mesh Headings (Keywords): Amino Acids, Animals, Binding Sites, Botulinum Toxins, Catalysis, Humans, Metalloproteases, Models, Molecular, Neurotoxins, Protein Binding, Protein Structure, Quaternary, Substrate Specificity, Synaptosomal-Associated Protein 25, Zinc
Check for Full Text / PubMed Unique Identifier (PMID): 17609207
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