Synthesis, 3-D structure, and pharmacology of a reticulated chimeric peptide derived from maurotoxin and Tsk scorpion toxins.
Maurotoxin (MTX) is a 34-mer scorpion toxin cross-linked by four disulfide bridges that acts on both Ca(2+)-activated (SK) and voltage-gated (Kv) K(+) channels. A 38-mer chimera of MTX, Tsk-MTX, has been synthesized by the solid-phase method. It encompasses residues from 1 to 6 of Tsk at N-terminal, and residues from 3 to 34 of MTX at C-terminal. As established by enzyme cleavage, Tsk-MTX displays half-cystine pairings of the type C1-C5, C2-C6, C3-C7 and C4-C8 which, contrary to MTX, correspond to a disulfide bridge pattern common to known scorpion toxins. The 3-D structure of Tsk-MTX, solved by (1)H NMR, demonstrates that it adopts the alpha/beta scaffold of scorpion toxins. In vivo, Tsk-MTX is lethal by intracerebroventricular injection in mice (LD(50) value of 0.2 microg/mouse). In vitro, Tsk-MTX is as potent as MTX, or Tsk, to interact with apamin-sensitive SK channels of rat brain synaptosomes (IC(50) value of 2.5 nM). It also blocks voltage-gated K(+) channels expressed in Xenopus oocytes, but is inactive on rat Kv1.3 contrary to MTX.
Fajloun
Ziad
Z
Boulevard Pierre Dramard, CNRS UMR 6560, 13916 Marseille Cedex 20, France.
Ferrat
Gilles
G
Carlier
Edmond
E
M'Barek
Sarrah
S
Regaya
Imed
I
Fathallah
Mohamed
M
Rochat
Hervé
H
Darbon
Hervé
H
de Waard
Michel
M
Sabatier
Jean-Marc
JM
D000595:Amino Acid Sequence; D000818:Animals; D004220:Disulfides / Q000737:chemistry; D006860:Hydrogen Bonding; D007700:Kinetics; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009498:Neurotoxins / Q000737:chemistry / Q000494:pharmacology; D019906:Nuclear Magnetic Resonance, Biomolecular; D009865:Oocytes / Q000378:metabolism; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D026902:Potassium Channel Blockers / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D017433:Protein Structure, Secondary; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D012604:Scorpion Venoms / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D017386:Sequence Homology, Amino Acid; D014981:Xenopus
D004220:Disulfides; D009498:Neurotoxins; D010455:Peptides; D026902:Potassium Channel Blockers; D011993:Recombinant Fusion Proteins; D012604:Scorpion Venoms; C110355:TsKapa; C104498:maurotoxin; C450722:toxin Tskapa-maurotoxin