Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 110, Issue 22, Pages 8906-8911Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1214062110
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Funding
- Australian Research Council [855]
- Institute for Molecular Bioscience Postgraduate Award
- National Health and Medical Research Council (NHMRC) [351446]
- NHMRC [569927, APP1019761, 569918, 471418]
- Fonds Wetenschappelijk Onderzoek Vlaanderen [G.0433.12]
- Inter-University Attraction Poles Program, Belgian State, Belgian Science Policy [IUAP 7/10]
- Katholieke Universiteit Leuven [OT/12/081]
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We recently reported the isolation of a scorpion toxin named U-1-liotoxin-Lw1a (U-1-LITX-Lw1a) that adopts an unusual 3D fold termed the disulfide-directed hairpin (DDH) motif, which is the proposed evolutionary structural precursor of the three-disulfide-containing inhibitor cystine knot (ICK) motif found widely in animals and plants. Here we reveal that U-1-LITX-Lw1a targets and activates the mammalian ryanodine receptor intracellular calcium release channel (RyR) with high (fM) potency and provides a functional link between DDH and ICK scorpion toxins. Moreover, U-1-LITX-Lw1a, now described as phi-liotoxin-Lw1a (phi-LITX-Lw1a), has a similar mode of action on RyRs as scorpion calcines, although with significantly greater potency, inducing full channel openings at lower (fM) toxin concentrations whereas at higher pM concentrations increasing the frequency and duration of channel openings to a submaximal state. In addition, we show that the C-terminal residue of phi-LITX-Lw1a is crucial for the increase in full receptor openings but not for the increase in receptor subconductance opening, thereby supporting the two-binding-site hypothesis of scorpion toxins on RyRs. phi-LITX-Lw1a has potential both as a pharmacological tool and as a lead molecule for the treatment of human diseases that involve RyRs, such as malignant hyperthermia and polymorphic ventricular tachycardia.
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