Hadrucalcin

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Modeled 3D structure of Hadrucalcin

Hadrucalcin is a peptide toxin from the venom of the scorpion Hadrurus gertschi.[1] Hadrucalcin modifies the Ryanodine receptor channels RyR1 and RyR2, found in the sarcoplasmic reticulum, to a long-lasting subconductance state, thus inducing the release of calcium from the sarcoplasmic reticulum.[2]

Source and etymology[edit]

Hadrucalcin (HdCa, alternative spelling: Hadrucalcine) is obtained from the venom gland of the scorpion Hadrurus gertschi,[2] endemic to Guerrero, Mexico.[3] Hadrucalcin is named after the scorpion that produces the peptide and its similarity to other toxins of the scorpion calcin family.[2]

Chemistry[edit]

Hadrucalcin is a peptide toxin from the scorpion calcin family.[1] The mature hadrucalcin peptide is composed of 35 amino acids, whereas other members of the scorpion calcin family are composed of 33 amino acids.[2] Based on the high degree of sequence similarity with maurocalcin, it is predicted that hadrucalcin folds along an inhibitor cystine knot motif,[2] with disulfide bonds between positions 5 and 19, 12 and 23 and 18 and 34 of the mature peptide.[1] Hadrucalcin has a molecular weight of 4190.5 Da.[2] The most notable difference between hadrucalcin and other members of the scorpion calcin family is that hadrucalcin lacks two positive charged lysine residues (at positions 8 and 22 in other scorpion calcine toxins),[2] that were previously thought to be important for affinity with RyR1.[4] Instead, Hadrucalcin has two Lysine residues at positions 3 and 7 of the mature peptide, near the otherwise neutral N-terminal, resulting in a relatively low degree of amphiphilicity.[2]

01 02 03 04 05 06 07 08 09 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 21 32 33 34 35
HdCa[1] S E K D C I K H L Q R C R E N K D C C S K K C S R R G T N P E K R C R
MCa[5] G D C L P H L K L C K E N K D C C S K K C K R R G T N I E K R C R
01 02 03 04 05 06 07 08 09 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 21 32 33
Linear amino acid sequence of mature Hadrucalcin (HdCa) and Maurocalcin (MCa)

Target and Mode of Action[edit]

Hadrucalcin targets ryanodine receptor channels RyR1 and RyR2, found in the sarcoplasmic reticulum of skeletal muscle cells and cardiac muscle cells respectively.[1] By inducing a long-lasting subconductance state in RyR1 (35% of full conductance) and RyR2 (50% of full conductance), hadrucalcin increases the total ion flow over these channels.[2] Within a few seconds, hadrucalcin is able to permeate the cell membrane of ventricular myocytes and induce the release of calcium from the sarcoplasmic reticulum.[2] Despite functional effects on both channels, hadrucalcin only enhances the binding of ryanodine to RyR1 (EC50 = 37.8nM Hadrucalcin), but not to RyR2, suggesting the binding sites for hadrucalcin are structurally different in RyR1 and RyR2.[2] The exact interacting sites of hadrucalcin on the ryanodine receptors are unknown.

Therapeutic Use[edit]

Maurocalcin is the first proven example of a scorpion toxin that can act as a vector for large compounds.[6] Hadrucalcin appears to be an even more potent cell penetrating peptide.[7] A Hadrucalcin derivative has been used as a carrier for nanobiosensors.[8]

References[edit]

  1. ^ a b c d e "Hadrucalcin precursor - Hoffmannihadrurus gertschi (Scorpion)".
  2. ^ a b c d e f g h i j k Schwartz EF, Capes EM, Diego-García E, et al. Characterization of hadrucalcin, a peptide from Hadrurus gertschi scorpion venom with pharmacological activity on ryanodine receptors. Br J Pharmacol. 2009;157(3):392-403. doi:10.1111/j.1476-5381.2009.00147.x.
  3. ^ Soleglad ME. The Taxonomy of the Genus Hadrurus Based on Chela Trichobothria (Scorpionida: Vejovidae). J Arachnol. 1976;3:113-134. doi:10.2307/3705291.
  4. ^ Lee CW, Lee EH, Takeuchi K, et al. Molecular basis of the high-affinity activation of type 1 ryanodine receptors by imperatoxin A. Biochem J. 2004;377(Pt 2):385-94. doi:10.1042/BJ20031192.
  5. ^ "UniProt". www.uniprot.org. Archived from the original on 2016-10-11.
  6. ^ Estève E, Mabrouk K, Dupuis A, et al. Transduction of the scorpion toxin maurocalcine into cells. Evidence that the toxin crosses the plasma membrane. J Biol Chem. 2005;280(13):12833-9. doi:10.1074/jbc.M412521200.
  7. ^ Tisseyre C, Bahembera E, Dardevet L, Sabatier J-M, Ronjat M, De Waard M. Cell penetration properties of a highly efficient mini maurocalcine Peptide. Pharmaceuticals (Basel). 2013;6(3):320-39. doi:10.3390/ph6030320.
  8. ^ Zamaleeva AI, Collot M, Bahembera E, et al. Cell-Penetrating Nanobiosensors for Pointillistic Intracellular Ca 2+ - Transient Detection. 2014.
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