Glycine 30 in iberiotoxin is a critical determinant of its specificity for maxi-K versus K(V) channels.
Iberiotoxin (IbTX) is a remarkably selective alpha-K toxin peptide (alpha-KTx) inhibitor of the maxi-K channel. In contrast, the highly homologous charybdotoxin inhibits both the maxi-K and K(V)1.3 channels with similar high affinity. The present study investigates the molecular basis for this specificity through mutagenesis of IbTX. The interactions of mutated peptides with maxi-K and K(V)1.3 channels were monitored through dose-dependent displacement of specifically bound iodinated alpha-KTx peptides from membranes expressing these channels. Results of these studies suggest that the presence of a glycine at position 30 in IbTX is a major determinant of its specificity while the presence of four unique acidic residues in IbTX is not.
Schroeder
Nathan
N
Department of Biochemistry, Temple University School of Medicine, 3420 N. Broad Street, Philadelphia, PA 19140, USA.
Mullmann
Theodore J
TJ
Schmalhofer
W A
WA
Gao
Ying-Duo
YD
Garcia
Maria L
ML
Giangiacomo
Kathleen M
KM
D000595:Amino Acid Sequence; D001216:Asparagine; D002478:Cells, Cultured; D005998:Glycine / Q000737:chemistry*; D006801:Humans; D051664:Kv1.3 Potassium Channel; D051036:Large-Conductance Calcium-Activated Potassium Channels; D008969:Molecular Sequence Data; D009154:Mutation; D010455:Peptides / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015221:Potassium Channels / Q000378:metabolism*; D024681:Potassium Channels, Calcium-Activated / Q000378:metabolism*; D024642:Potassium Channels, Voltage-Gated; D011487:Protein Conformation; D012604:Scorpion Venoms / Q000235:genetics / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D013379:Substrate Specificity; D014118:Toxins, Biological / Q000378:metabolism*
C496973:KCNA3 protein, human; D051664:Kv1.3 Potassium Channel; D051036:Large-Conductance Calcium-Activated Potassium Channels; D010455:Peptides; D015221:Potassium Channels; D024681:Potassium Channels, Calcium-Activated; D024642:Potassium Channels, Voltage-Gated; D012604:Scorpion Venoms; D014118:Toxins, Biological; D001216:Asparagine; C064719:iberiotoxin; C052567:noxiustoxin; D005998:Glycine