Definition of the M-Conotoxin Superfamily:  Characterization of Novel Peptides from Molluscivorous Conus Venoms

Abstract

Most of the >50,000 different pharmacologically active peptides in Conus venoms belong to a small number of gene superfamilies. In this work, the M-conotoxin superfamily is defined using both biochemical and molecular criteria. Novel excitatory peptides purified from the venoms of the molluscivorous species Conus textile and Conus marmoreus all have a characteristic pattern of Cys residues previously found in the mu-, kappaM-, and psi-conotoxins (CC-C-C-CC). The new peptides are smaller (12-19 amino acids) than the mu-, kappaM-, and psi-conotoxins (22-24 amino acids). One peptide, mr3a, was chemically synthesized in a biologically active form. Analysis of the disulfide bridges of a natural peptide tx3c from C. textile and synthetic peptide mr3a from C. marmoreus showed a novel pattern of disulfide connectivity, different from that previously established for the mu- and psi-conotoxins. Thus, these peptides belong to a new group of structurally and pharmacologically distinct conotoxins that are particularly prominent in the venoms of mollusc-hunting Conus species. Analysis of cDNA clones encoding the novel peptides as well as those encoding mu-, kappaM-, and psi-conotoxins revealed highly conserved amino acid residues in the precursor sequences; this conservation in both amino acid sequence and in the Cys pattern defines a gene superfamily, designated the M-conotoxin superfamily. The peptides characterized can be provisionally assigned to four distinct groups within the M-superfamily based on sequence similarity within and divergence between each group. A notable feature of the superfamily is that two distinct structural frameworks have been generated by changing the disulfide connectivity on an otherwise conserved Cys pattern.

Functional Hypervariability and Gene Diversity of Cardioactive Neuropeptides

“…A sequence similarity search (46) detected homologies with the precursors of CCAP from arthropods as well as L. gigantea (21) (supplemental Table S1). The conoCAP-a precursor contained two other related CAPs: conoCAP-b and conoCAP-c. All conoCAP peptides are predicted to be C-terminally amidated, because Gly is present at the loci preceding the C-terminal cleavage site (47).…”

ConusPeptides: Biodiversity-based Discovery and Exogenomics

“…Peptides of the same superfamily generally share a characteristic arrangement of Cys residues in the mature toxin region (the "Cys pattern"); each Cys pattern usually corresponds to a specific disulfide framework. However, in two gene superfamilies, each with a conserved Cys pattern, the disulfide connectivity changed as spacing of amino acids between Cys residues changed (15,16). Thus, although peptides in a gene superfamily usually have similar structures, groups of peptides with new disulfide scaffolds can occasionally evolve within a superfamily.…”

Conotoxins: from the biodiversity of gastropods to new drugs

“…далее) и d-конотоксины (действие этих токсинов замедляет или блокирует быструю инактивацию Na-каналов) [2,42]. Антагонисты кальциевых каналов широко известны по w-конотоксину GVIA.…”

“…Антагонисты кальциевых каналов широко известны по w-конотоксину GVIA. w-Конотоксины блокируют синаптическую нервно-мышечную передачу, с чем связано их активное применение в нейрофизиологии [42,43]. Блокаторы калиевых каналов, k-и kМ-конотоксины, характеризуются исключительным разнообразием структуры и на настоящий момент остаются слабо изучены.…”