A membrane-access mechanism of ion channel inhibition by voltage sensor toxins from spider venom.
Venomous animals produce small protein toxins that inhibit ion channels with high affinity. In several well-studied cases the inhibitory proteins are water-soluble and bind at a channel's aqueous-exposed extracellular surface. Here we show that a voltage-sensor toxin (VSTX1) from the Chilean Rose Tarantula (Grammostola spatulata) reaches its target by partitioning into the lipid membrane. Lipid membrane partitioning serves two purposes: to localize the toxin in the membrane where the voltage sensor resides and to exploit the free energy of partitioning to achieve apparent high-affinity inhibition. VSTX1, small hydrophobic poisons and anaesthetic molecules reveal a common theme of voltage sensor inhibition through lipid membrane access. The apparent requirement for such access is consistent with the recent proposal that the sensor in voltage-dependent K+ channels is located at the membrane-protein interface.
Lee
Seok-Yong
SY
The Howard Hughes Medical Institute and Rockefeller University, 1230 York Avenue, New York, New York 10021, USA.
MacKinnon
Roderick
R
D000595:Amino Acid Sequence; D000818:Animals; D002462:Cell Membrane / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D004594:Electrophysiology; D005453:Fluorescence; D015640:Ion Channel Gating / Q000187:drug effects*; D008563:Membrane Lipids / Q000378:metabolism; D008954:Models, Biological; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D024642:Potassium Channels, Voltage-Gated / Q000378:metabolism*; D013111:Spider Venoms / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D014364:Tryptophan
D008563:Membrane Lipids; D010455:Peptides; D024642:Potassium Channels, Voltage-Gated; D013111:Spider Venoms; C487989:VSTX1 protein, Grammostola spatulata; D014364:Tryptophan