Insights into the different catalytic activities of Clostridium neurotoxins

Research output: Journal Publications and Reviews (RGC: 21, 22, 62)21_Publication in refereed journal

18 Scopus Citations
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Author(s)

  • Sheng Chen
  • Andrew P. A. Karalewitz
  • Joseph T. Barbieri

Detail(s)

Original languageEnglish
Pages (from-to)3941-3947
Journal / PublicationBiochemistry
Volume51
Issue number18
Online published24 Apr 2012
Publication statusPublished - 8 May 2012
Externally publishedYes

Abstract

The clostridial neurotoxins are among the most potent protein toxins for humans and are responsible for botulism, a flaccid paralysis elicited by the botulinum toxins (BoNT), and spastic paralysis elicited by tetanus toxin (TeNT). Seven serotypes of botulinum neurotoxins (A-G) and tetanus toxin showed different toxicities and cleave their substrates with different efficiencies. However, the molecular basis of their different catalytic activities with respect to their substrates is not clear. BoNT/B light chain (LC/B) and TeNT light chain (LC/T) cleave vesicle-associated membrane protein 2 (VAMP2) at the same scissile bond but possess different catalytic activities and substrate requirements, which make them the best candidates for studying the mechanisms of their different catalytic activities. The recognition of five major P sites of VAMP2 (P7, P6, P1, P1′, and P2′) and fine alignment of sites P2 and P3 and sites P2 and P4 by LC/B and LC/T, respectively, contributed to their substrate recognition and catalysis. Significantly, we found that the S1 pocket mutation LC/T(K168E) increased the rate of native VAMP2 cleavage so that it approached the rate of LC/B, which explains the molecular basis for the lower kcat that LC/T possesses for VAMP2 cleavage relative to that of LC/B. This analysis explains the molecular basis underlying the VAMP2 recognition and cleavage by LC/B and LC/T and provides insight that may extend the pharmacologic utility of these neurological reagents.

Citation Format(s)

Insights into the different catalytic activities of Clostridium neurotoxins. / Chen, Sheng; Karalewitz, Andrew P. A.; Barbieri, Joseph T.

In: Biochemistry, Vol. 51, No. 18, 08.05.2012, p. 3941-3947.

Research output: Journal Publications and Reviews (RGC: 21, 22, 62)21_Publication in refereed journal