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Structure of botulinurn neurotoxin type d light chain at 1.65 Å resolution: Repercussions for vamp-2 substrate specificity

Academic Article
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Overview

authors

  • Arndt, J. W.
  • Chai, Q.
  • Christian, T.
  • Stevens, Raymond

publication date

  • March 2006

journal

  • Biochemistry  Journal

abstract

  • The seven serotypes (A-G) of botulinum neurotoxins (BoNTs) function through their proteolytic cleavage of one of three proteins (SNAP-25, Syntaxin, and VAMP) that form the SNARE complex required for synaptic vesicle fusion. The different BoNTs have very specific protease recognition requirements, between 15 and 50 amino acids in length depending on the serotype. However, the structural details involved in substrate recognition remain largely unknown. Here is reported the 1.65 A resolution crystal structure of the catalytic domain of BoNT serotype D (BoNT/D-LC), providing insight into the protein-protein binding interaction and final proteolysis of VAMP-2. Structural analysis has identified a hydrophobic pocket potentially involved in substrate recognition of the P1' VAMP residue (Leu 60) and a second remote site for recognition of the V1 SNARE motif that is critical for activity. A structural comparison of BoNT/D-LC with BoNT/F-LC that also recognizes VAMP-2 one residue away from the BoNT/D-LC site provides additional molecular details about the unique serotype specific activities. In particular, BoNT/D prefers a hydrophobic interaction for the V1 motif of VAMP-2, while BoNT/F adopts a more hydrophilic strategy for recognition of the same V1 motif.

subject areas

  • Amino Acid Motifs
  • Amino Acid Sequence
  • Animals
  • Binding Sites
  • Botulinum Toxins
  • Clostridium botulinum
  • Crystallography, X-Ray
  • Hydrophobic and Hydrophilic Interactions
  • Models, Genetic
  • Models, Molecular
  • Molecular Sequence Data
  • Protein Conformation
  • Recombinant Fusion Proteins
  • SNARE Proteins
  • Schistosoma japonicum
  • Substrate Specificity
  • Synaptosomal-Associated Protein 25
  • Vesicle-Associated Membrane Protein 2
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Identity

International Standard Serial Number (ISSN)

  • 0006-2960

Digital Object Identifier (DOI)

  • 10.1021/bi052518r

PubMed ID

  • 16519520
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Additional Document Info

start page

  • 3255

end page

  • 3262

volume

  • 45

issue

  • 10

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