Intrepicalcin

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Intrepicalcin (ViCaTx1) is a short peptide toxin found in the venom of scorpion Vaejovis intrepidus. It is one of a group of short, basic peptides called calcins, which bind to ryanodine receptors (RyRs) and thereby trigger calcium release from the sarcoplasmic reticulum.

Contents

Etymology

The name intrepicalcin is a combination of the species name of the organism that produces it ( Vaejovis intrepidus) and the family name of short toxins that it belongs to (calcins).

Source

Intrepicalcin is a toxin derived from the venom gland of the scorpion Vaejovis intrepidus  [1] . This species belongs to the family of Vaejovidae in the order of Scorpiones. [2] Vaejovis intrepidus is endemic to central Mexico. [3]

Chemistry

Structure and family

Intrepicalcin (ViCaTx1) belongs to the scorpion calcin family. The structure of calcins is specified by the Inhibitor Cystine Knot (ICK) motif. This folding motif is found in many toxins interacting with calcium channels in spiders and snails and distinguishes them from sodium, potassium and chloride channel toxins in scorpions. All calcins are composed of 33 amino acids, among which are 6 cysteines. These cysteines are highly conserved and form three disulfide bonds that are important for the ICK motif. In intrepicalcin and some other calcins, three of these cysteines are embedded in three 𝛽 strands. [4] [2]

The 3D structure of intrepicalcin has not yet been solved. However, the 3D structure of imperacalcin, another member of the calcin family, has been elucidated with 1H-NMR. [5] Based on the fact that intrepicalcin and imperacalcin have a 70% sequence homology (see Homology), it is predicted that intrepicalcin has a coiled, spherical structure. [2] The ICK motif contains three disulfide bridges embedded in 𝛽 strands. Most positively-charged residues (lysine and arginine) are located on the frontal side of the peptide. However, compared to other calcins, intrepicalcin contains two extra positively-charged basic lysines (residue 12 and 14) on its dorsal side. Therefore, its charge separation is the lowest of all calcins. [2]

Homology

The most closely related calcin is vejocalcin, which only differs in its 14th residue (N in vejocalcin versus K in intrepicalcin) and has a matching identity of 97.0%. [2] Imperacalcin, on the other hand, has a matching identity of only 69.7% (ten different residues) and has the lowest similarity with intrepicalcin of all currently known members of the calcin family. This suggests that within this family, intrepicalcin and imperacalcin have the smallest common evolutionary origin. Furthermore, in general the C-terminal part of the calcin peptide (residues 15-33), containing two of the cysteine-containing 𝛽 strands, is relatively conserved compared to the N-terminal part (residues 1-14). The C-terminal part thus also shows more homology across the calcin family than the N-terminal part. [2]

Target

Intrepicalcin exerts its toxic effect by binding to ryanodine receptor 1 (RyR1), which is a calcium release ion channel present in mammalian skeletal muscle cells. [6] RyR1s can be opened by direct protein-protein interaction with dihydropyridine receptors, which are voltage-sensing L-type calcium channels (CaV1.1). [6] When the muscle depolarizes, a conformational change in CaV1.1 activates RyR1, which then opens and allows calcium release from the sarcoplasmic reticulum. [7] This phenomenon is called coupled gating. RyR1s seem to be able to open without this interaction as well, but the underlying mechanism is not yet fully understood. [6] RyR1 consists of four subunits and has binding sites for several regulatory molecules, such as calcium, calmodulin, ATP and magnesium. The opening of the channel involves two hinge glycines. The receptor is expressed in mammals, but homologues exist in avian and amphibian skeletal muscles. [6]

Mode of action

Intrepicalcin stabilizes the opening of RyR1 and brings it into a reversible and long-lasting subconductance state. This subconductance state is 55% of the full conductance state of the channel and enables a constant calcium release from the sarcoplasmic reticulum. [2] [8] The precise binding site of intrepicalcin on RyR1 is not known. However, imperacalcin is known to bind a site within the ion conduction channel. Since all known calcins induce the same modifications, a common binding site seems likely. [2] Intrepicalcin and calcins in general are able to cross the plasma membrane and can thus translocate between cells. [9] [2]

Toxicity

The ryanodine receptor 1 (RyR1) is expressed in skeletal muscles in mammals. [2] The alterations in the calcium potentials which are caused by intrepicalcin interaction with RyR1, affect these skeletal muscles and result in muscular paralysis. This can contribute to the immobilization of the predators and preys of the scorpion Vaejovis intrepidus. [2] [9]

Related Research Articles

<span class="mw-page-title-main">Sarcoplasmic reticulum</span> Menbrane-bound structure in muscle cells for storing calcium

The sarcoplasmic reticulum (SR) is a membrane-bound structure found within muscle cells that is similar to the smooth endoplasmic reticulum in other cells. The main function of the SR is to store calcium ions (Ca2+). Calcium ion levels are kept relatively constant, with the concentration of calcium ions within a cell being 10,000 times smaller than the concentration of calcium ions outside the cell. This means that small increases in calcium ions within the cell are easily detected and can bring about important cellular changes (the calcium is said to be a second messenger). Calcium is used to make calcium carbonate (found in chalk) and calcium phosphate, two compounds that the body uses to make teeth and bones. This means that too much calcium within the cells can lead to hardening (calcification) of certain intracellular structures, including the mitochondria, leading to cell death. Therefore, it is vital that calcium ion levels are controlled tightly, and can be released into the cell when necessary and then removed from the cell.

Ryanodine receptors form a class of intracellular calcium channels in various forms of excitable animal tissue like muscles and neurons. There are three major isoforms of the ryanodine receptor, which are found in different tissues and participate in different signaling pathways involving calcium release from intracellular organelles. The RYR2 ryanodine receptor isoform is the major cellular mediator of calcium-induced calcium release (CICR) in animal cells.

A calcium spark is the microscopic release of calcium (Ca2+) from a store known as the sarcoplasmic reticulum (SR), located within muscle cells. This release occurs through an ion channel within the membrane of the SR, known as a ryanodine receptor (RyR), which opens upon activation. This process is important as it helps to maintain Ca2+ concentration within the cell. It also initiates muscle contraction in skeletal and cardiac muscles and muscle relaxation in smooth muscles. Ca2+ sparks are important in physiology as they show how Ca2+ can be used at a subcellular level, to signal both local changes, known as local control, as well as whole cell changes.

<span class="mw-page-title-main">Ryanodine receptor 2</span> Transport protein and coding gene in humans

Ryanodine receptor 2 (RYR2) is one of a class of ryanodine receptors and a protein found primarily in cardiac muscle. In humans, it is encoded by the RYR2 gene. In the process of cardiac calcium-induced calcium release, RYR2 is the major mediator for sarcoplasmic release of stored calcium ions.

Ca<sub>v</sub>1.1 Mammalian protein found in Homo sapiens

Cav1.1 also known as the calcium channel, voltage-dependent, L type, alpha 1S subunit, (CACNA1S), is a protein which in humans is encoded by the CACNA1S gene. It is also known as CACNL1A3 and the dihydropyridine receptor.

<span class="mw-page-title-main">Triadin</span> Protein-coding gene in humans

Triadin, also known as TRDN, is a human gene associated with the release of calcium ions from the sarcoplasmic reticulum triggering muscular contraction through calcium-induced calcium release. Triadin is a multiprotein family, arising from different processing of the TRDN gene on chromosome 6. It is a transmembrane protein on the sarcoplasmic reticulum due to a well defined hydrophobic section and it forms a quaternary complex with the cardiac ryanodine receptor (RYR2), calsequestrin (CASQ2) and junctin proteins. The luminal (inner compartment of the sarcoplasmic reticulum) section of Triadin has areas of highly charged amino acid residues that act as luminal Ca2+ receptors. Triadin is also able to sense luminal Ca2+ concentrations by mediating interactions between RYR2 and CASQ2. Triadin has several different forms; Trisk 95 and Trisk 51, which are expressed in skeletal muscle, and Trisk 32 (CT1), which is mainly expressed in cardiac muscle.

<span class="mw-page-title-main">Ryanodine receptor 1</span> Protein and coding gene in humans

Ryanodine receptor 1 (RYR-1) also known as skeletal muscle calcium release channel or skeletal muscle-type ryanodine receptor is one of a class of ryanodine receptors and a protein found primarily in skeletal muscle. In humans, it is encoded by the RYR1 gene.

<span class="mw-page-title-main">Maurocalcine</span> Protein

Maurocalcine (MCa) is a protein, 33 Amino acid residues in length, isolated from the venom of the scorpion Maurus palmatus, which belongs to the family Chactidae, first characterized in 2000. The toxin is present in such small amounts that it could not be isolated to analyze it, so a chemical synthesis of this toxin was performed by the solid-phase technique so it could be fully characterized. It shares 82% sequence identity with imperatoxin A (IpTx A), a scorpion toxin from the venom of Pandinus imperator. IpTx A acts by modifying the activity of the type 1 ryanodine receptor of skeletal muscle. RyR controls the intracellular Ca2+ permeability of various cell types and is central in the process of excitation–contraction of muscle tissues. The synthesized toxin, sMCa is active on RyR1 and it binds onto a site different from that of ryanodine itself.

Imperatoxin I (IpTx) is a peptide toxin derived from the venom of the African scorpion Pandinus imperator.

Birtoxin is a neurotoxin from the venom of the South African Spitting scorpion. By changing sodium channel activation, the toxin promotes spontaneous and repetitive firing much like pyrethroid insecticides do

Helothermine is a toxin from the venom of the Mexican beaded lizard Heloderma horridum horridum. Helothermine inhibits ryanodine receptors, calcium channels and potassium channels. Helothermine can cause lethargy, partial paralysis of rear limbs and lowering of the body temperature.

<span class="mw-page-title-main">Hadrucalcin</span> Peptide toxin from the venom of the scorpion Hadrurus gertschi

Hadrucalcin is a peptide toxin from the venom of the scorpion Hadrurus gertschi. 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.

The ryanodine-inositol 1,4,5-triphosphate receptor Ca2+ channel (RIR-CaC) family includes Ryanodine receptors and Inositol trisphosphate receptors. Members of this family are large proteins, some exceeding 5000 amino acyl residues in length. This family belongs to the Voltage-gated ion channel (VIC) superfamily. Ry receptors occur primarily in muscle cell sarcoplasmic reticular (SR) membranes, and IP3 receptors occur primarily in brain cell endoplasmic reticular (ER) membranes where they effect release of Ca2+ into the cytoplasm upon activation (opening) of the channel. They are redox sensors, possibly providing a partial explanation for how they control cytoplasmic Ca2+. Ry receptors have been identified in heart mitochondria where they provide the main pathway for Ca2+ entry. Sun et al. (2011) have demonstrated oxygen-coupled redox regulation of the skeletal muscle ryanodine receptor-Ca2+ release channel (RyR1;TC# 1.A.3.1.2) by NADPH oxidase 4.

Pi4 is a short toxin from the scorpion Pandinus imperator that blocks specific potassium channels.

<span class="mw-page-title-main">Noxiustoxin</span> Toxin from the venom of the scorpion Centruroides noxius

Noxiustoxin (NTX) is a toxin from the venom of the Mexican scorpion Centruroides noxius Hoffmann which block voltage-dependent potassium channels and calcium-activated potassium channels.

<span class="mw-page-title-main">Wasabi receptor toxin</span>

Wasabi receptor toxin (WaTx) is the active component of the venom of the Australian black rock scorpion Urodacus manicatus. WaTx targets TRPA1, also known as the wasabi receptor or irritant receptor. WaTx is a cell-penetrating toxin that stabilizes the TRPA1 channel open state while reducing its Ca2+-permeability, thereby eliciting pain and pain hypersensitivity without the neurogenic inflammation that typically occurs in other animal toxins.

<span class="mw-page-title-main">Vejocalcin</span> Toxin

Vejocalcin (VjCa, also called Vejocalcine) is a toxin from the venom of the Mexican scorpion Vaejovis mexicanus. Vejocalcin is a member of the calcin family of toxins. It acts as a cell-penetrating peptide (CPP); it binds with high affinity and specificity to skeletal ryanodine receptor 1 (RYR1) of the sarcoplasmic reticulum, thereby triggering calcium release from intracellular Ca2+ stores.

LmαTX5 is an α-scorpion toxin which inhibits the fast inactivation of voltage-gated sodium channels. It has been identified through transcriptome analysis of the venom gland of Lychas mucronatus, also known as the Chinese swimming scorpion – a scorpion species which is widely distributed in Southeast Asia.

Tb1 is a neurotoxin that is naturally found in the venom of the Brazilian scorpion Tityus bahiensis. Presumably by acting on voltage-gated sodium channels, it triggers excessive glutamate release, which can lead to both behavioral and electrographic epileptiform alterations, as well as neuronal injury.

κ-KTx2.5 is a toxin found in the venom of the scorpion, Opisthacanthuscayaporum. The toxin belongs to the κ-KTx family, a channel blocker family that targets voltage-gated potassium channels (Kv) 1.1 and 1.4.

References

  1. ↑ Quintero-Hernández, Verónica; Ramírez-Carreto, Santos; Romero-Gutiérrez, María Teresa; Valdez-Velázquez, Laura L.; Becerril, Baltazar; Possani, Lourival D.; Ortiz, Ernesto (2015). "Transcriptome Analysis of Scorpion Species Belonging to the Vaejovis Genus". PLOS ONE. 10 (2): e0117188. Bibcode:2015PLoSO..1017188Q. doi: 10.1371/journal.pone.0117188 . ISSN   1932-6203. PMC   4319844 . PMID   25659089.
  2. 1 2 3 4 5 6 7 8 9 10 11 Vargas-Jaimes, Leonel; Xiao, Liang; Zhang, Jing; Possani, Lourival D.; Valdivia, Héctor H.; Quintero-Hernández, Verónica (2017). "Recombinant expression of Intrepicalcin from the scorpion Vaejovis intrepidus and its effect on skeletal ryanodine receptors". Biochimica et Biophysica Acta (BBA) - General Subjects. 1861 (4): 936–946. doi:10.1016/j.bbagen.2017.01.032. ISSN   0006-3002. PMC   5329131 . PMID   28159581.
  3. ↑ Santibáñez-López, Carlos E.; Francke, Oscar F.; Ureta, Carolina; Possani, Lourival D. (2015). "Scorpions from Mexico: From Species Diversity to Venom Complexity". Toxins. 8 (1): 2. doi: 10.3390/toxins8010002 . ISSN   2072-6651. PMC   4728524 . PMID   26712787.
  4. ↑ Ramos-Franco, Josefina; Fill, Michael (2016). "Approaching ryanodine receptor therapeutics from the calcin angle". The Journal of General Physiology. 147 (5): 369–373. doi:10.1085/jgp.201611599. ISSN   0022-1295. PMC   4845691 . PMID   27114611.
  5. ↑ Lee, Chul Won; Lee, Eun Hui; Takeuchi, Koh; Takahashi, Hideo; Shimada, Ichio; Sato, Kazuki; Shin, Song Yub; Kim, Do Han; Kim, Jae Il (2004). "Molecular basis of the high-affinity activation of type 1 ryanodine receptors by imperatoxin A." Biochemical Journal. 377 (Pt 2): 385–394. doi:10.1042/BJ20031192. ISSN   0264-6021. PMC   1223873 . PMID   14535845.
  6. 1 2 3 4 Meissner, Gerhard (2017). "The structural basis of ryanodine receptor ion channel function". The Journal of General Physiology. 149 (12): 1065–1089. doi:10.1085/jgp.201711878. ISSN   0022-1295. PMC   5715910 . PMID   29122978.
  7. ↑ Proenza, Catherine; O'Brien, Jennifer; Nakai, Junichi; Mukherjee, Santwana; Allen, Paul D.; Beam, Kurt G. (2002). "Identification of a Region of RyR1 That Participates in Allosteric Coupling with the α1S (CaV1.1) II–III Loop". Journal of Biological Chemistry. 277 (8): 6530–6535. doi: 10.1074/jbc.M106471200 . ISSN   0021-9258. PMID   11726651.
  8. ↑ "Intrepicalcin precursor - Thorellius intrepidus (Scorpion)". www.uniprot.org. Retrieved 2019-10-06.
  9. 1 2 Schwartz, Elisabeth F; Capes, E Michelle; Diego-García, Elia; Zamudio, Fernando Z; Fuentes, Oscar; Possani, Lourival D; Valdivia, Héctor H (2009). "Characterization of hadrucalcin, a peptide from Hadrurus gertschi scorpion venom with pharmacological activity on ryanodine receptors". British Journal of Pharmacology. 157 (3): 392–403. doi:10.1111/j.1476-5381.2009.00147.x. ISSN   0007-1188. PMC   2707986 . PMID   19389159.
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