Multiple actions of phi-LITX-Lw1a on ryanodine receptors reveal a functional link between scorpion DDH and ICK toxins

Jennifer J. Smith, Irina Vetter, Richard J. Lewis, Steve Peigneur, Jan Tytgat, Alexander Lam, Esther M. Gallant, Nicole BEARD, Paul F. Alewood, Angela F. Dulhunty

    Research output: Contribution to journalArticle

    25 Citations (Scopus)

    Abstract

    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
    Original languageEnglish
    Pages (from-to)8906-8911
    Number of pages6
    JournalNational Academy of Sciences. Proceedings
    Volume110
    Issue number22
    DOIs
    Publication statusPublished - 2013

    Fingerprint

    Scorpions
    Ryanodine Receptor Calcium Release Channel
    Cystine
    Disulfides
    Cystine Knot Motifs
    Malignant Hyperthermia
    Ventricular Tachycardia
    Binding Sites
    Pharmacology

    Cite this

    Smith, Jennifer J. ; Vetter, Irina ; Lewis, Richard J. ; Peigneur, Steve ; Tytgat, Jan ; Lam, Alexander ; Gallant, Esther M. ; BEARD, Nicole ; Alewood, Paul F. ; Dulhunty, Angela F. / Multiple actions of phi-LITX-Lw1a on ryanodine receptors reveal a functional link between scorpion DDH and ICK toxins. In: National Academy of Sciences. Proceedings. 2013 ; Vol. 110, No. 22. pp. 8906-8911.
    @article{c1d2a3c3349a4150a5915094d8291036,
    title = "Multiple actions of phi-LITX-Lw1a on ryanodine receptors reveal a functional link between scorpion DDH and ICK toxins",
    abstract = "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",
    keywords = "Skeletal muscle, calcium channels, toxins",
    author = "Smith, {Jennifer J.} and Irina Vetter and Lewis, {Richard J.} and Steve Peigneur and Jan Tytgat and Alexander Lam and Gallant, {Esther M.} and Nicole BEARD and Alewood, {Paul F.} and Dulhunty, {Angela F.}",
    year = "2013",
    doi = "10.1073/pnas.1214062110",
    language = "English",
    volume = "110",
    pages = "8906--8911",
    journal = "National Academy of Sciences. Proceedings",
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    Smith, JJ, Vetter, I, Lewis, RJ, Peigneur, S, Tytgat, J, Lam, A, Gallant, EM, BEARD, N, Alewood, PF & Dulhunty, AF 2013, 'Multiple actions of phi-LITX-Lw1a on ryanodine receptors reveal a functional link between scorpion DDH and ICK toxins', National Academy of Sciences. Proceedings, vol. 110, no. 22, pp. 8906-8911. https://doi.org/10.1073/pnas.1214062110

    Multiple actions of phi-LITX-Lw1a on ryanodine receptors reveal a functional link between scorpion DDH and ICK toxins. / Smith, Jennifer J.; Vetter, Irina; Lewis, Richard J.; Peigneur, Steve; Tytgat, Jan; Lam, Alexander; Gallant, Esther M.; BEARD, Nicole; Alewood, Paul F.; Dulhunty, Angela F.

    In: National Academy of Sciences. Proceedings, Vol. 110, No. 22, 2013, p. 8906-8911.

    Research output: Contribution to journalArticle

    TY - JOUR

    T1 - Multiple actions of phi-LITX-Lw1a on ryanodine receptors reveal a functional link between scorpion DDH and ICK toxins

    AU - Smith, Jennifer J.

    AU - Vetter, Irina

    AU - Lewis, Richard J.

    AU - Peigneur, Steve

    AU - Tytgat, Jan

    AU - Lam, Alexander

    AU - Gallant, Esther M.

    AU - BEARD, Nicole

    AU - Alewood, Paul F.

    AU - Dulhunty, Angela F.

    PY - 2013

    Y1 - 2013

    N2 - 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

    AB - 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

    KW - Skeletal muscle

    KW - calcium channels

    KW - toxins

    U2 - 10.1073/pnas.1214062110

    DO - 10.1073/pnas.1214062110

    M3 - Article

    VL - 110

    SP - 8906

    EP - 8911

    JO - National Academy of Sciences. Proceedings

    JF - National Academy of Sciences. Proceedings

    SN - 0027-8424

    IS - 22

    ER -