8.B.16 The Membrance-pentitrating, Ryanodine Receptor-activating Maurocalcine (MaCa) Family
Maurocalcine (maurocalcin) (MCa) is a 33-amino acid residue peptide that was initially identified in the Tunisian scorpion, Scorpion maurus palmatus. This peptide triggers interest for three main reasons. First, it helps unravelling the mechanistic basis of Ca2+ mobilization from the sarcoplasmic reticulus because of its sequence homology with a calcium channel domain in excitation-contraction coupling. Second, it shows potent pharmacological properties because of its ability to activate the ryanodine receptor. Finally, it is of technological value because of its ability to carry cell-impermeable compounds across the plasma membrane. Mabrouk et al., 2007 characterized the molecular determinants that underlie the pharmacological and cell-penetrating properties of maurocalcin. They identify several key amino acid residues of the peptide that determine cell penetrability. Basic amino acid residues are required for an interaction with negatively charged lipids of the plasma membrane. Maurocalcine analogues that penetrate better have stronger interactions with negatively charged lipids.
Maurocalcine (maurocalcin; MCa) of the scorpion. The 3-d structure is known (1C6W_A) (Mabrouk et al., 2007). This toxin stabilizes ryanodine receptor 1 (RyR1) opening in a long-lasting subconductance state (48%-60% of the full conductance state) (Fajloun et al. 2000, Xiao et al. 2016). Furthermore, it triggers calcium release from sarcoplasmic vesicles. Cryo-EM analysis of scorpion toxin binding to Ryanodine Receptors reveals a subconductance that is abolished by PKA phosphorylation (Haji-Ghassemi et al. 2023).
Maurocalcin of Maurus palmatus (P60254)
Egg protein of 92 aas
Animals (flat worms)
Egg protein of Scizosoma japonicum (blood fluke)
Hadrucalcin of 74 aas. A knottin. Activates both skeletal ryanodine receptors (RYR1) and cardiac ryanodine receptors (RYR2) by inducing a long-lasting subconductance state, rapidly permeating the external membrane of cardiomyocytes and inducing calcium release from intracellular stores. Acts synergistically with caffeine (Schwartz et al. 2009).
Hadrucalcin of Hadrurus gertschi
Ω-hexatosin-Hv1e (Ω-Alracotoxin-Hv1e), a knottin of 37 aas. The 3-d structure of a synthetic construct of similar sequence is availalbe (1HVW_A).
hexatoxin of Hadronyche versuta or Atrax versutus (funnel web spider)
Kappa conotoxin sr11aof 32 aas. It inhibits several potassium channels such as Kv1.1, 1.2, 1.3, and 1.6 (Robinson and Norton 2014).
Conotoxin sr11a of Conus spurius (Alphabet cone)
Gamma-conotoxin PnVIIA of 80 aas and 1 TMS. It may act on voltage-gated non-specific cation pacemaker channels (HCN). It triggers depolarization and firing of action potential bursts in the caudodorsal neurons of lymnaea. This effect is due to activation or enhancement of a slow inward cation current that may underlie endogenous bursting activity of these neurons (Fainzilber et al. 1998).
γ-conotoxin of Conus pennaceus (Feathered cone) (Conus episcopus)
Gamma-conotoxin-like TeA53 of 81 aas.
γ-conotoxin of Conus textile (Cloth-of-gold cone)
Contryphan_M_precursor_1 of 63 aa
Contryphan of Conus marmoreus
Alpha-conotoxin-like Rt20.2 of 92 aas with 1 N-terminal TMS. Alpha-conotoxins act on postsynaptic membranes,;they bind to the nicotinic acetylcholine receptors (nAChR) and thus inhibit them. This toxin specifically blocks mammalian neuronal nAChR of the alpha-7/CHRNA7, alpha-3-beta-2/CHRNA3-CHRNB2 and alpha-4-beta-2/CHRNA4-CHRNB2 subtypes.α-conotoxin
α-Conotoxin of Conus rattus (Rat cone)
Conotoxin family Q, partial of 64 aas and 1 N-terminal TMS.
Conotoxing family Q of Conus ermineus (Atlantic fish-hunting cone)
N-type conotoxin Mr15.2 of 92 aas and 1 TMSs (Dutertre et al. 2013).
CoTx15.2 of Conus marmoreus
Iota-conotoxin precursor of 82 aas and 1 N-terminal TMS. Iota contoxin RXIA is 46 aas and activates Nav1.6 and Nav1.2 voltage-gated sodium channels (VGSC). It contains an inhibitory cystein knot and a D-amino acid. It contains the cysteine motif: C-C-CC-CC-C-C as do other members of the family (Robinson and Norton 2014).
Iota conotoxin of Conus radiatus (Rayed cone)
Conotoxin ca11a of 80 aas and 1 N-terminal TMS.
Conotoxin ca11a of Conus caracteristicus (Characteristic cone)
Teretoxin Tsu15.4 of 77 aas (Gorson et al. 2015).
Teretoxin of Terebra subulata