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Science 11 November 1994:
Vol. 266. no. 5187, pp. 1065 - 1068
DOI: 10.1126/science.7973665
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Articles

Science, Vol 266, Issue 5187, 1065-1068
Copyright © 1994 by American Association for the Advancement of Science

articles

Functional consequences of posttranslational isomerization of Ser46 in a calcium channel toxin

SD Heck, CJ Siok, KJ Krapcho, PR Kelbaugh, PF Thadeio, MJ Welch, RD Williams, AH Ganong, ME Kelly, AJ Lanzetti, and al. et

NPS Pharmaceuticals Incorporated, Salt Lake City, Utah 84108.

The venom of the funnel-web spider Agelenopsis aperta contains several peptides that paralyze prey by blocking voltage-sensitive calcium channels. Two peptides, omega-Aga-IVB (IVB) and omega-Aga-IVC (IVC), have identical amino acid sequences, yet have opposite absolute configurations at serine 46. These toxins had similar selectivities for blocking voltage-sensitive calcium channel subtypes but different potencies for blocking P-type voltage-sensitive calcium channels in rat cerebellar Purkinje cells as well as calcium-45 influx into rat brain synaptosomes. An enzyme purified from venom converts IVC to IVB by isomerizing serine 46, which is present in the carboxyl-terminal tail, from the L to the D configuration. Unlike the carboxyl terminus of IVC, that of IVB was resistant to the major venom protease. These results show enzymatic activities in A. aperta venom being used in an unprecedented strategy for coproduction of necessary neurotoxins that possess enhanced stability and potency.


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