Alpha4/3 conotoxins: phylogenetic distribution, functional properties, and structure-function insights.
This review examines the alpha4/3 conotoxins as an example of molecular diversity in a class of compounds that have evolved in a group of closely related species in a single phylogenetic lineage. The species examined belong to Stephanoconus, a clade of Conus, a genus that contains 500-700 different species of carnivorous marine snails. We examine earlier work that describes the identification and characterization of alpha-ImI, the founding alpha4/3 toxin, and two other alpha4/3 toxins, alpha-ImII and alpha-RgIA. These three toxins all inhibit nicotinic acetylcholine receptors (nAChRs) belonging to a subset of nAChRs that are composed of only alpha subunits; they are, however, diverse in terms of the all-alpha subtype they preferentially antagonize and the receptor site that they bind to. We thus speculate that the alpha4/3 toxins may be a rich source of functionally diverse all-alpha subunit nAChR inhibitors. We review extensive work that has established a detailed model for alpha-ImI binding to one of its preferred nAChR subtypes (the alpha7 nAChR) and, by comparing the alpha-ImI, alpha-ImII and alpha-RgIA sequences demonstrate how structural features of alpha4/3 peptides that account for their diverse functional properties can be identified. This approach is extended to derive models of receptor-toxin binding that may account for the different subtype specificities of alpha4/3 peptides. We also speculate on how rational modification of alpha4/3 toxins may allow engineering of ligands with desired subtype specificities. The chemical diversity produced by the closely related animals in Stephanoconus is thus functionally differentiated, although structurally homologous.
Department of Biology, University of Utah, Salt Lake City, Utah, 84112, USA. Michael.Ellison@m.cc.utah.edu
Michael
M
Ellison
Baldomero M
BM
Olivera
D000595:Amino Acid Sequence; D000818:Animals; D020916:Conotoxins / Q000737:chemistry* / Q000145:classification / Q000494:pharmacology; D008969:Molecular Sequence Data; D008974:Mollusca; D010802:Phylogeny; D011978:Receptors, Nicotinic / Q000187:drug effects; D013045:Species Specificity; D013329:Structure-Activity Relationship
D020916:Conotoxins; D011978:Receptors, Nicotinic