M2 Proton Channel: Difference between revisions
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<StructureSection load='1nyj' size='340' side='right' caption='The closed state structure of M2 protein H+ channel by solid state NMR spectroscopy ([[1nyj]])' scene=''> | |||
== M2 Proton Channel from ''Influenza'' A Virus == | == M2 Proton Channel from ''Influenza'' A Virus == | ||
== Background == | == Background == | ||
The M2 proton channel is a key protein that leads to viral infection.<ref name="Takeuchi" /> The M2 proton channel acidifies the virion which allows the viral matrix protein (M1) to disassociate from the ribonucleoprotein (RNP).<ref name="Wu">PMID:12972147 </ref> This allows the RNP to be transported to the nucleus of the cell. Several recent studies have looked at the effects of <scene name='User:Sarah_Henke/Sandbox_1/Amantadine/1'>amantadine</scene> ([[Symmetrel]])<ref name="Stouffer">PMID:18235504 </ref> and <scene name='User:Sarah_Henke/Sandbox_1/Rimantadine/1'>rimantadine</scene> ([[Flumadine]])<ref name="Schnell">PMID:18235503 </ref> on inhibiting the transfer of protons through the M2 channel.<ref name="Stouffer" /> Amantadine is a proton surrogate that competes with protons for binding to His37, the residue involved in the gating mechanism.<ref name="Lear" /> It has been found that M2 is resistant to these two drugs in 90% of humans, birds and pigs. Understanding the structure and function of this proton channel is necessary in solving the resistance problem.<ref name="Stouffer" /> | The M2 proton channel is a key protein that leads to viral infection.<ref name="Takeuchi" /> The M2 proton channel acidifies the virion which allows the viral matrix protein (M1) to disassociate from the ribonucleoprotein (RNP).<ref name="Wu">PMID:12972147 </ref> This allows the RNP to be transported to the nucleus of the cell. Several recent studies have looked at the effects of <scene name='User:Sarah_Henke/Sandbox_1/Amantadine/1'>amantadine</scene> ([[Symmetrel]])<ref name="Stouffer">PMID:18235504 </ref> and <scene name='User:Sarah_Henke/Sandbox_1/Rimantadine/1'>rimantadine</scene> ([[Flumadine]])<ref name="Schnell">PMID:18235503 </ref> on inhibiting the transfer of protons through the M2 channel.<ref name="Stouffer" /> Amantadine is a proton surrogate that competes with protons for binding to His37, the residue involved in the gating mechanism.<ref name="Lear" /><ref>PMID:3662473</ref><ref>PMID:17156962</ref> It has been found that M2 is resistant to these two drugs in 90% of humans, birds and pigs. Understanding the structure and function of this proton channel is necessary in solving the resistance problem.<ref name="Stouffer" /> | ||
== Animation of Opening and Closing == | |||
A [[morph]] animation of the H2 proton channel opening and closing is available at [[Proton Channels]]. | |||
== Structure == | == Structure == | ||
The M2 proton channel from influenza A is 97 amino acid residues and forms a 24-residue N-terminal extracellular domain, a 19-residue trans-membrane domain, and a 54-residue C-terminal cytoplasmic domain.<ref name="Wu" /> The 19-residue TM domain forms the highly selective proton channel.<ref name="Takeuchi">PMID:12972149 </ref> Circular dichroism spectra has shown the TM domain to form an <scene name='User:Sarah_Henke/Sandbox_1/Momomer/2'>α-helix</scene> that spans the membrane.<ref name="Wu" /> By analytical ultracentrifugation, the TM domain is found to form <scene name='User:Sarah_Henke/Sandbox_1/Alpha_hlix/1'>homotetramers</scene> which contains four identical α-helices.<ref name="Takeuchi" /> Secondary structure is color coded by the following, if present: {{Template:ColorKey_Helix}}, {{Template:ColorKey_Strand}}, and {{Template:ColorKey_Turn}}. When viewed in the <scene name='User:Sarah_Henke/Sandbox_1/N_to_c/1'>N->C color coding</scene> the <FONT COLOR="blue">'''N-terminus'''</FONT> (see scale below) is located near the external side of the membrane while the <FONT COLOR="red">'''C-terminus'''</FONT> is located near the internal side of the membrane, closest to the virion. This tetrameric bundle of the TM domain is found by NMR to be tilted by 25-38° from the channel axis. The tetrameric helices form a left-handed bundle that resembles a truncated cone. The TM helicies are arranged around the channel pore with an approximate four-fold rotational symmetry.<ref name="Takeuchi" /> | The M2 proton channel from influenza A is 97 amino acid residues and forms a 24-residue N-terminal extracellular domain, a 19-residue trans-membrane domain, and a 54-residue C-terminal cytoplasmic domain.<ref name="Wu" /> The 19-residue TM domain forms the highly selective proton channel.<ref name="Takeuchi">PMID:12972149 </ref> Circular dichroism spectra has shown the TM domain to form an <scene name='User:Sarah_Henke/Sandbox_1/Momomer/2'>α-helix</scene> that spans the membrane.<ref name="Wu" /> By analytical ultracentrifugation, the TM domain is found to form <scene name='User:Sarah_Henke/Sandbox_1/Alpha_hlix/1'>homotetramers</scene> which contains four identical α-helices.<ref name="Takeuchi" /> Secondary structure is color coded by the following, if present: {{Template:ColorKey_Helix}}, {{Template:ColorKey_Strand}}, and {{Template:ColorKey_Turn}}. When viewed in the <scene name='User:Sarah_Henke/Sandbox_1/N_to_c/1'>N->C color coding</scene> the <FONT COLOR="blue">'''N-terminus'''</FONT> (see scale below) is located near the external side of the membrane while the <FONT COLOR="red">'''C-terminus'''</FONT> is located near the internal side of the membrane, closest to the virion. This tetrameric bundle of the TM domain is found by NMR to be tilted by 25-38° from the channel axis. The tetrameric helices form a left-handed bundle that resembles a truncated cone. The TM helicies are arranged around the channel pore with an approximate four-fold rotational symmetry.<ref name="Takeuchi" /> | ||
{{Template:ColorKey_N2CRainbow}} | {{Template:ColorKey_N2CRainbow}} | ||
== Central Cavity == | == Central Cavity == | ||
The hydrophilic residues in each α-helix monomer are oriented towards the pore lumen. The <scene name='User:Sarah_Henke/Sandbox_1/Hydrophobic/2'>hydrophobic</scene> residues will be in contact with the membrane (Color code= {{Template:ColorKey_Hydrophobic}} or {{Template:ColorKey_Polar}}). Most of the residues in the M2 channel are hydrophobic except Ser31 Gly34, and His37.<ref name="Wu" /> The central cavity of the M2 proton channel is most constricted near residue <scene name='User:Sarah_Henke/Sandbox_1/Val27/1'>Val27</scene>. After this residue, the cavity opens to a water-filled pore that is lined with residues <scene name='User:Sarah_Henke/Sandbox_1/Pore/1'>Ala30, Ser31, and Gly34</scene>.<ref name="Stouffer" /> Mutagenesis studies have found that the residues facing the pore are Val27, Ala30, Ser31, Gly34, His37, Leu38, and Trp41.<ref name="Wu" /> The central cavity also constricts at residues His37 and Trp41.<ref name="Stouffer" /> Residues <scene name='User:Sarah_Henke/Sandbox_1/His_37/1'>His37</scene> and <scene name='User:Sarah_Henke/Sandbox_1/Trp20/1'>Trp41</scene> play a key role in the gating mechanism.<ref name="Wu" /> In the closed state, the <scene name='User:Sarah_Henke/Sandbox_1/Histrp/1'>His37 and Trp41</scene> residues block the channel, preventing proton conductance. <ref name="Lear">PMID:12972146 </ref> | The hydrophilic residues in each α-helix monomer are oriented towards the pore lumen. The <scene name='User:Sarah_Henke/Sandbox_1/Hydrophobic/2'>hydrophobic</scene> residues will be in contact with the membrane (Color code= {{Template:ColorKey_Hydrophobic}} or {{Template:ColorKey_Polar}}). Most of the residues in the M2 channel are hydrophobic except Ser31 Gly34, and His37.<ref name="Wu" /> The central cavity of the M2 proton channel is most constricted near residue <scene name='User:Sarah_Henke/Sandbox_1/Val27/1'>Val27</scene>. After this residue, the cavity opens to a water-filled pore that is lined with residues <scene name='User:Sarah_Henke/Sandbox_1/Pore/1'>Ala30, Ser31, and Gly34</scene>.<ref name="Stouffer" /> Mutagenesis studies have found that the residues facing the pore are Val27, Ala30, Ser31, Gly34, His37, Leu38, and Trp41.<ref name="Wu" /> The central cavity also constricts at residues His37 and Trp41.<ref name="Stouffer" /> Residues <scene name='User:Sarah_Henke/Sandbox_1/His_37/1'>His37</scene> and <scene name='User:Sarah_Henke/Sandbox_1/Trp20/1'>Trp41</scene> play a key role in the gating mechanism.<ref name="Wu" /> In the closed state, the <scene name='User:Sarah_Henke/Sandbox_1/Histrp/1'>His37 and Trp41</scene> residues block the channel, preventing proton conductance. <ref name="Lear">PMID:12972146 </ref> | ||
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== Selectivity == | == Selectivity == | ||
Because the N-terminus is very constricted near Val27, the M2 channel is highly selective for protons. | Because the N-terminus is very constricted near Val27, the M2 channel is highly selective for protons. The restricted N-terminus only allows protons to penetrate into the aqueous pore through hydrogen-bonded chains of water. Therefore, it would be extremely difficult for hydrated sodium or potassium to penetrate the restricted areas of the M2 channel.<ref name="Stouffer" /> | ||
==3D structures of proton channel== | |||
See proton channel in [[Ion channels]] | |||
==Additional Resources== | ==Additional Resources== | ||
*[[Proton Channels]] includes a morph animation of the H2 proton channel opening and closing. | |||
*[[Membrane Channels & Pumps]] | |||
<br /> | <br /> | ||
*[[Rimantadine]]<br /> | |||
*[[Amantadine]]<br /> | |||
*[[Treatments:M2 Proton Channel Inhibitor Pharmacokinetics]]<br /> | |||
*[[Treatments:Influenza]]. | |||
</StructureSection> | |||
== References == | == References == | ||
<references /> | <references /> | ||