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== Structure == | == Structure == | ||
Biologically, Ectatomin exists as a heterodimer stabilized by <scene name='69/691538/Cysteine_disulfide/1'>disulfide | Biologically, Ectatomin exists as a heterodimer stabilized by <scene name='69/691538/Cysteine_disulfide/1'>disulfide bonds</scene>. The <scene name='69/691538/Alpha_subunit/1'>α subunit</scene> has 37 amino acid residues, while the <scene name='69/691538/Beta_subunit/1'>β subunit</scene> has 34 amino acid residues. The structure of Ectatomin was determined using [https://en.wikipedia.org/wiki/Two-dimensional_nuclear_magnetic_resonance_spectroscopy 2D NMR] and [https://en.wikipedia.org/wiki/CHARMM CHARMm] computational optimization, though there are 20 similar proposed models in total.<ref name="refone">PMID: 7881269</ref> | ||
Generally, each subunit is composed of two antiparallel α-helices, linked by disulfide bonds, with a connecting hairpin hinge region. The two subunits are linked by a disulfide bond between their hairpin hinge regions. One α-helix from each subunit is kinked approximately 40°, due to the presence of <scene name='69/691538/Prolines_both_subunits/2'>proline residues</scene>. The kinked α-helix of the α subunit is more kinked, containing three proline residues, while the kinked α-helix of the β subunit only contains one proline residue.<ref name="refone" /> | Generally, each subunit is composed of two antiparallel α-helices, linked by disulfide bonds, with a connecting hairpin hinge region. The two subunits are linked by a disulfide bond between their hairpin hinge regions. One α-helix from each subunit is kinked approximately 40°, due to the presence of <scene name='69/691538/Prolines_both_subunits/2'>proline residues</scene>. The kinked α-helix of the α subunit is more kinked, containing three proline residues, while the kinked α-helix of the β subunit only contains one proline residue.<ref name="refone" /> | ||
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== Toxicology == | == Toxicology == | ||
With an [https://en.wikipedia.org/wiki/Median_lethal_dose LD<sub>50</sub>] of 6.8 μg kg<sup>-1</sup>, Ectatomin is one of the deadliest proteins known to man, alongside [https://en.wikipedia.org/wiki/Tetanospasmin Tetanospasmin] and the [https://en.wikipedia.org/wiki/Botulinum_toxin Botulinum toxin].<ref name="refthree" /> Ectatomin attacks and forms pores in the plasma membrane, sometimes irreversibly, allowing cations to freely | With an [https://en.wikipedia.org/wiki/Median_lethal_dose LD<sub>50</sub>] of 6.8 μg kg<sup>-1</sup>, Ectatomin is one of the deadliest proteins known to man, alongside [https://en.wikipedia.org/wiki/Tetanospasmin Tetanospasmin] and the [https://en.wikipedia.org/wiki/Botulinum_toxin Botulinum toxin].<ref name="refthree" /> Ectatomin attacks and forms pores in the plasma membrane, sometimes irreversibly, allowing cations to freely diffuse through the cell membrane.<ref name="refone" /> The primary cations which flow through the pore are Ca<sup>2+</sup> and K<sup>+</sup>. Physiologically, the primary targets of Ectatomin are muscle, particularly the heart, and neuronal cells. As the cation concentration equilibrates between the two sides of the cell membrane, the affected cells lose their ability to form and maintain a [https://en.wikipedia.org/wiki/Membrane_potential membrane potential] and concentration gradient.<ref name="reftwo" /> Without the ability to form a calcium or potassium gradient, muscle cells are not able to contract and the target is rendered paralyzed. This is particularly dangerous when the heart is affected as it halts the circulatory system.<ref name="reftwo" /> When neurons are affected, the inability to maintain and form a membrane potential eliminates the ability of the neuron to receive and transmit information.<ref name="reffour" />. Either of these issues can easily result in death to the cell and the organism. | ||
== Mechanism == | == Mechanism == | ||
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Ectatomin has several proposed mechanisms of action. The primary proposed mechanism involves the formation of a nonselective cation channel. In this mechanism, the α and β subunits open up, exposing the internal hydrophobic residues.<ref name="refone" /> The protein flattens while remaining attached at the hairpin hinge region. The now exposed hydrophobic residues nonselectively insert into plasma membranes.<ref name="refone" /> The inserted protein dimerizes, eventually forming a nonselective cation channel.<ref name="refthree" /> | Ectatomin has several proposed mechanisms of action. The primary proposed mechanism involves the formation of a nonselective cation channel. In this mechanism, the α and β subunits open up, exposing the internal hydrophobic residues.<ref name="refone" /> The protein flattens while remaining attached at the hairpin hinge region. The now exposed hydrophobic residues nonselectively insert into plasma membranes.<ref name="refone" /> The inserted protein dimerizes, eventually forming a nonselective cation channel.<ref name="refthree" /> | ||
For the second and third proposed mechanisms of action, Ectatomin has also been shown to inhibit kinases, specifically protein tyrosine kinase and protein kinase C, and natural Ca<sup>2+</sup> channels. Kinase inhibition would | For the second and third proposed mechanisms of action, Ectatomin has also been shown to inhibit kinases, specifically protein tyrosine kinase and protein kinase C, and natural Ca<sup>2+</sup> channels. Kinase inhibition would allow Ectatomin to interfere with various components of [https://en.wikipedia.org/wiki/Signal_transduction signal transduction].<ref name="refthree" /> Calcium channel inhibition would allow Ectatomin to affect physiological processes such as contraction, neurotransmitter release and neuronal activity regulation.<ref name="reffour">PMID: 24929139</ref> | ||
== References == | == References == | ||
<references/> | <references/> | ||
Latest revision as of 00:55, 2 April 2015
Ectatomin (1eci) is the main component of venom of the ant Ectatomma tuberculatum, making up 15%-18% of the crude venom and accounting for 90% of the venom's toxicity.[1] When bitten by E. tuberculatum, Ectatomin inserts into the target's cell membranes and forms a nonselective cation channel.[2] The calculated isoelectric point and molecular weight of Ectatomin are 9.95 and 7928 Da, respectively.[1] While the biology regarding Ectatomin production and toxicity is not fully understood, several in vitro studies have been performed and mechanisms have been postulated.
|
StructureStructure
Biologically, Ectatomin exists as a heterodimer stabilized by . The has 37 amino acid residues, while the has 34 amino acid residues. The structure of Ectatomin was determined using 2D NMR and CHARMm computational optimization, though there are 20 similar proposed models in total.[3]
Generally, each subunit is composed of two antiparallel α-helices, linked by disulfide bonds, with a connecting hairpin hinge region. The two subunits are linked by a disulfide bond between their hairpin hinge regions. One α-helix from each subunit is kinked approximately 40°, due to the presence of . The kinked α-helix of the α subunit is more kinked, containing three proline residues, while the kinked α-helix of the β subunit only contains one proline residue.[3]
The internal region between the two subunits is primarily composed of hydrophobic residues.
Sequence - α subunit - GVIPKKIWETVCPTVEPWAKKCSGDIATYIKRECGKL[2]
Sequence - β subunit - WSTIVKLTICPTLKSMAKKCEGSIATMIKKKCDK[2]
ToxicologyToxicology
With an LD50 of 6.8 μg kg-1, Ectatomin is one of the deadliest proteins known to man, alongside Tetanospasmin and the Botulinum toxin.[1] Ectatomin attacks and forms pores in the plasma membrane, sometimes irreversibly, allowing cations to freely diffuse through the cell membrane.[3] The primary cations which flow through the pore are Ca2+ and K+. Physiologically, the primary targets of Ectatomin are muscle, particularly the heart, and neuronal cells. As the cation concentration equilibrates between the two sides of the cell membrane, the affected cells lose their ability to form and maintain a membrane potential and concentration gradient.[2] Without the ability to form a calcium or potassium gradient, muscle cells are not able to contract and the target is rendered paralyzed. This is particularly dangerous when the heart is affected as it halts the circulatory system.[2] When neurons are affected, the inability to maintain and form a membrane potential eliminates the ability of the neuron to receive and transmit information.[4]. Either of these issues can easily result in death to the cell and the organism.
MechanismMechanism
Ectatomin has several proposed mechanisms of action. The primary proposed mechanism involves the formation of a nonselective cation channel. In this mechanism, the α and β subunits open up, exposing the internal hydrophobic residues.[3] The protein flattens while remaining attached at the hairpin hinge region. The now exposed hydrophobic residues nonselectively insert into plasma membranes.[3] The inserted protein dimerizes, eventually forming a nonselective cation channel.[1]
For the second and third proposed mechanisms of action, Ectatomin has also been shown to inhibit kinases, specifically protein tyrosine kinase and protein kinase C, and natural Ca2+ channels. Kinase inhibition would allow Ectatomin to interfere with various components of signal transduction.[1] Calcium channel inhibition would allow Ectatomin to affect physiological processes such as contraction, neurotransmitter release and neuronal activity regulation.[4]
ReferencesReferences
- ↑ 1.0 1.1 1.2 1.3 1.4 Arseniev AS, Pluzhnikov KA, Nolde DE, Sobol AG, Torgov MYu, Sukhanov SV, Grishin EV. Toxic principle of selva ant venom is a pore-forming protein transformer. FEBS Lett. 1994 Jun 27;347(2-3):112-6. PMID:8033986
- ↑ 2.0 2.1 2.2 2.3 2.4 Pluzhnikov K, Nosyreva E, Shevchenko L, Kokoz Y, Schmalz D, Hucho F, Grishin E. Analysis of ectatomin action on cell membranes. Eur J Biochem. 1999 Jun;262(2):501-6. PMID:10336635
- ↑ 3.0 3.1 3.2 3.3 3.4 Nolde DE, Sobol AG, Pluzhnikov KA, Grishin EV, Arseniev AS. Three-dimensional structure of ectatomin from Ectatomma tuberculatum ant venom. J Biomol NMR. 1995 Jan;5(1):1-13. PMID:7881269
- ↑ 4.0 4.1 Touchard A, Labriere N, Roux O, Petitclerc F, Orivel J, Escoubas P, Koh JM, Nicholson GM, Dejean A. Venom toxicity and composition in three Pseudomyrmex ant species having different nesting modes. Toxicon. 2014 Sep;88:67-76. doi: 10.1016/j.toxicon.2014.05.022. Epub 2014 Jun 11. PMID:24929139 doi:http://dx.doi.org/10.1016/j.toxicon.2014.05.022