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J. Biol. Chem., Vol. 279, Issue 17, 17596-17606, April 23, 2004
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From the
Departments of Biology, ¶Psychiatry, and **Pathology, University of Utah, Salt Lake City, Utah 84112 and the National Institute of Molecular Biology and Biotechnology and the Marine Science Institute, University of the Philippines, Diliman, Quezon City 1101, Philippines
The generation of functional novelty in proteins encoded by a gene superfamily is seldom well documented. In this report, we define the A-conotoxin superfamily, which is widely expressed in venoms of the predatory cone snails (Conus), and show how gene products that diverge considerably in structure and function have arisen within the same superfamily. A cDNA clone encoding 
-conotoxin GI, the first conotoxin characterized, provided initial data that identified the A-superfamily. Conotoxin precursors in the A-superfamily were identified from six Conus species: most (11/16) encoded -conotoxins, but some (5/16) belong to a family of excitatory peptides, the 
A-conotoxins that target voltage-gated ion channels. -Conotoxins are two-disulfide-bridged nicotinic antagonists, 13–19 amino acids in length; A-conotoxins are larger (31–36 amino acids) with three disulfide bridges. Purification and biochemical characterization of one peptide, A-conotoxin MIVA is reported; five of the other predicted conotoxins were previously venom-purified. A comparative analysis of conotoxins purified from venom, and their precursors reveal novel post-translational processing, as well as mutational events leading to polymorphism. Patterns of sequence divergence and Cys codon usage define the major superfamily branches and suggest how these separate branches arose.
Received for publication, September 2, 2003 , and in revised form, December 26, 2003.
* This work was supported in part by Program Project GM-48677 from the National Institutes of Health. A preliminary account of some of this work was presented in an unpublished thesis (30) as well as in the patent literature (Olivera et al. (12/31/96), Process and primers for identifying nucleic acids encoding A-lineage conotoxin peptides, U.S. Patent 5,589,340 (33)). Two of the sequences in the unpublished thesis were independently discovered by Bai-Song et al. (31). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
|| Also supported by National Institutes of Health Grant MH-53631.
To whom correspondence should be addressed: Dept. of Biology, University of Utah, 257 S. 1400 E., Salt Lake City, UT 84112. Tel.: 801-581-8370; Fax: 801-585-5010; E-mail: olivera{at}biology.utah.edu.
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