Phylogenetic specificity of cholinergic ligands: alpha-conotoxin SI.
The alpha-conotoxins are small peptide neurotoxins from the venom of fish-hunting cone snails which block nicotinic acetylcholine receptors (nAChRs). We describe the purification, characterization, and chemical synthesis of a new alpha-conotoxin from Conus striatus, alpha-conotoxin SI. In contrast to other AChR ligands, alpha-SI discriminates between different vertebrate nAChRs. The sequence of alpha-conotoxin SI is Ile-Cys-Cys-Asn-Pro5-Ala-Cys-Gly-Pro-Lys10-Tyr-Ser-Cys-NH2. This sequence was confirmed by chemical synthesis. A des-Ile-alpha-SI derivative was also synthesized and is biologically active. Although alpha-conotoxin SI is highly homologous to previously described alpha-conotoxins, it has one noteworthy sequence feature which may account for its novel biological specificity. In all other alpha-conotoxins, there is a positively charged amino acid at residue 9; in alpha-conotoxin SI, this is replaced by proline. The discovery that different alpha-conotoxins can vary by orders of magnitude in their apparent affinity for different vertebrate receptors demonstrates that alpha-conotoxins will be useful probes for investigating phylogenetic differences between vertebrate nAChRs.
Zafaralla
G C
GC
Department of Biochemistry, University of the Philippines, Manila.
Ramilo
C
C
Gray
W R
WR
Karlstrom
R
R
Olivera
B M
BM
Cruz
L J
LJ
D000595:Amino Acid Sequence; D000818:Animals; D020916:Conotoxins; D008969:Molecular Sequence Data; D008978:Mollusk Venoms / Q000302:isolation & purification / Q000378:metabolism* / Q000494:pharmacology; D010802:Phylogeny; D011978:Receptors, Nicotinic / Q000378:metabolism*; D012908:Snails
D020916:Conotoxins; D008978:Mollusk Venoms; D011978:Receptors, Nicotinic; C057819:conotoxin SI