Definition of the M-conotoxin superfamily: characterization of novel peptides from molluscivorous Conus venoms.
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.
Corpuz
Gloria P
GP
Department of Biology, University of Utah, Salt Lake City, Utah 84112, USA.
Jacobsen
Richard B
RB
Jimenez
Elsie C
EC
Watkins
Maren
M
Walker
Craig
C
Colledge
Clark
C
Garrett
James E
JE
McDougal
Owen
O
Li
Wenqin
W
Gray
William R
WR
Hillyard
David R
DR
Rivier
Jean
J
McIntosh
J Michael
JM
Cruz
Lourdes J
LJ
Olivera
Baldomero M
BM
D000595:Amino Acid Sequence; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D003001:Cloning, Molecular; D020916:Conotoxins / Q000008:administration & dosage / Q000737:chemistry* / Q000145:classification* / Q000235:genetics / Q000302:isolation & purification; D018076:DNA, Complementary / Q000302:isolation & purification; D004220:Disulfides / Q000737:chemistry; D007276:Injections, Intraventricular; D051379:Mice; D008969:Molecular Sequence Data; D005810:Multigene Family; D010455:Peptides / Q000008:administration & dosage / Q000737:chemistry* / Q000235:genetics / Q000302:isolation & purification*; D013045:Species Specificity; D021241:Spectrometry, Mass, Electrospray Ionization; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
D020916:Conotoxins; D018076:DNA, Complementary; D004220:Disulfides; D010455:Peptides; C485418:conotoxin mr3a, Conus marmoreus