Sandbox WWC6: Difference between revisions
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Hemolysins are most commonly proteins found in red blood cells that selectively allow for the diffusion of potassium ions across the membrane. <ref >https://en.wikipedia.org/wiki/Hemolysin#cite_note-pmid20692229-3</ref> or lipid biosurfactants that disrupt membrane composition resulting in cell lysis. These proteins are important for some erythrocyte nutrient accession, but cause massive erythrocyte destruction in bacterial infection, specifically responsible forhemolytic anemia, which causes fatigue, pain, arrythmias, and even heart failure in affected individuals.<ref>http://www.nhlbi.nih.gov/health/health-topics/topics/ha/</ref> Each hemolysin pore is composed of three subunits: the alpha subunit, which is the transmembrane ion channel, and two beta subunits that modulate channel gating and regulate the channel expression in the membrane. <ref name ="beta">PMID: 11486343</ref> <ref name = "sod"/> The alpha subunit is able to function independently of the beta subunit. <ref name = "beta"/> | |||
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==Structure== | ==Structure== | ||
Hemolysins have three structural variations: alpha, beta, and gamma. These hemolysin types are comprised of di-, hepta- or octomeric subunits.<ref name = "sod"/> The alpha subunit, depicted right, consists of four repeating structures, named I through IV and shown in different colors <scene name='69/696300/Right_one/1'>here</scene>. <ref name ="struct"> DOI: 10.1111/j.1469-7793.1998.647bp.x </ref> These structures consist of six transmembrane alpha helices named S1 through S6. <ref name = "struct"/> Interestingly, each repeating subunit resembles a bacterial K<sup>+</sup> channel. <ref name = "struct"/> These subunits fold together to form a central pore, and this complete structure resembles a bacterial Ca2<sup>+</sup> channel. <ref name = "struct"/> | Hemolysins have three structural variations: alpha, beta, and gamma. These hemolysin types are comprised of di-, hepta- or octomeric subunits.<ref name = "sod"/> The alpha subunit, depicted right, consists of four repeating structures, named I through IV and shown in different colors <scene name='69/696300/Right_one/1'>here</scene>. <ref name ="struct"> DOI: 10.1111/j.1469-7793.1998.647bp.x </ref> These structures consist of six transmembrane alpha helices named S1 through S6. <ref name = "struct"/> Interestingly, each repeating subunit resembles a bacterial K<sup>+</sup> channel. <ref name = "struct"/> These subunits fold together to form a central pore, and this complete structure resembles a bacterial Ca2<sup>+</sup> channel. <ref name = "struct"/> | ||
===Alpha-hemolysin=== | |||
<scene name='69/696302/Alpha-hemolysin/1'>Alpha-hemolysin</scene> | <scene name='69/696302/Alpha-hemolysin/1'>Alpha-hemolysin</scene> | ||
===Beta-hemolysin=== | |||
<scene name='69/696302/Beta-hemolysin/2'>Beta-hemolysin</scene> | <scene name='69/696302/Beta-hemolysin/2'>Beta-hemolysin</scene> | ||
===Gamma-hemolysin=== | |||
<scene name='69/696302/Beta-hemolysin/1'>Gamma-hemolysin</scene> | <scene name='69/696302/Beta-hemolysin/1'>Gamma-hemolysin</scene> | ||
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[[Image:640px-Sodium-channel.png]] | [[Image:640px-Sodium-channel.png]] | ||
== | == Mechanism of action == | ||
The S1 through S4 segments make up the gating mechanism. <ref name= "crystal"/> In particular, the S4 segments consist of repeated motifs of a positively charged residue (usually Arg) followed by two hydrophobic residues. <ref name= "crystal"/> This alpha helix is exposed to the membrane electric field, and in response to a depolarization, it is displaced outwards, causing the channel to open.<ref name= "crystal"/> S4 segments can be seen in red <scene name='69/696300/S4/1'>here</scene>. Surprisingly, each S4 chain does not contribute equally to the gating of this channel. A mutation in one chain may have a much larger effect than a mutation in another S4 chain. <ref name= "crystal"/> However, these S4 segments are merely sensors. The actual gating mechanism is still up for debate, with the leading contender being the S6 segment. This mechanism would be similar to the gating of the K<sup>+</sup> channel. <ref name = "struct"/> The outward movement of the S4 segment moves the S4-S5 linker, which pulls the S5-S6 segments and opens the pore. <ref name= "crystal"/> Overall, the voltage sensing domain makes a rolling motion of the S4-S5 linker around the pore. <ref name= "crystal"/> The S4-S5 linker can be seen <scene name='69/696300/S4_s5_linker/2'>here</scene>. | The S1 through S4 segments make up the gating mechanism. <ref name= "crystal"/> In particular, the S4 segments consist of repeated motifs of a positively charged residue (usually Arg) followed by two hydrophobic residues. <ref name= "crystal"/> This alpha helix is exposed to the membrane electric field, and in response to a depolarization, it is displaced outwards, causing the channel to open.<ref name= "crystal"/> S4 segments can be seen in red <scene name='69/696300/S4/1'>here</scene>. Surprisingly, each S4 chain does not contribute equally to the gating of this channel. A mutation in one chain may have a much larger effect than a mutation in another S4 chain. <ref name= "crystal"/> However, these S4 segments are merely sensors. The actual gating mechanism is still up for debate, with the leading contender being the S6 segment. This mechanism would be similar to the gating of the K<sup>+</sup> channel. <ref name = "struct"/> The outward movement of the S4 segment moves the S4-S5 linker, which pulls the S5-S6 segments and opens the pore. <ref name= "crystal"/> Overall, the voltage sensing domain makes a rolling motion of the S4-S5 linker around the pore. <ref name= "crystal"/> The S4-S5 linker can be seen <scene name='69/696300/S4_s5_linker/2'>here</scene>. | ||
=== | ===Pore formation=== | ||
This channel conducts sodium at nearly the rate of free diffusion. <ref name= "crystal"/> This pore consists of an outer funnel-like vestibule, a selectivity filter, a central cavity, and an intracellular activation gate. <ref name= "crystal"/> Unlike the K<sup>+</sup> channel, the Na<sup>+</sup> channel conducts sodium ions that are hydrated with four water molecules. <ref name= "crystal"/> Much like with the gating mechanism, each domain does not contribute equally to the selectivity of the pore, but the channel selects for sodium 100x greater than it selects for any other ion. <ref name= "struct"/> | This channel conducts sodium at nearly the rate of free diffusion. <ref name= "crystal"/> This pore consists of an outer funnel-like vestibule, a selectivity filter, a central cavity, and an intracellular activation gate. <ref name= "crystal"/> Unlike the K<sup>+</sup> channel, the Na<sup>+</sup> channel conducts sodium ions that are hydrated with four water molecules. <ref name= "crystal"/> Much like with the gating mechanism, each domain does not contribute equally to the selectivity of the pore, but the channel selects for sodium 100x greater than it selects for any other ion. <ref name= "struct"/> | ||
It is likely that the sodium ion can get much closer to the channel entry than a larger K<sup>+</sup> ion. When the ion reaches this distance, there is a more efficient removal of water and the sodium interacts with the Glu117 side chains. Two side chains interact directly with the sodium ion and two additional side chains form hydrogen bonds with the water molecules <ref name= "crystal"/>. The pore is made up of T175, L176, E177 and S178. <ref name= "crystal"/> The Glu side chains act as hydrogen bond acceptors two in-plane molecules surrounding the sodium ion. <ref name= "crystal"/> The other two water molecules would be axial to the sodium ion. <ref name= "crystal"/> Full rehydration would occur when the ion moves next to the Leu and Thr residues. <ref name= "crystal"/> Full rehydration then allows the sodium ion to enter the cytoplasm. <ref name= "crystal"/> | It is likely that the sodium ion can get much closer to the channel entry than a larger K<sup>+</sup> ion. When the ion reaches this distance, there is a more efficient removal of water and the sodium interacts with the Glu117 side chains. Two side chains interact directly with the sodium ion and two additional side chains form hydrogen bonds with the water molecules <ref name= "crystal"/>. The pore is made up of T175, L176, E177 and S178. <ref name= "crystal"/> The Glu side chains act as hydrogen bond acceptors two in-plane molecules surrounding the sodium ion. <ref name= "crystal"/> The other two water molecules would be axial to the sodium ion. <ref name= "crystal"/> Full rehydration would occur when the ion moves next to the Leu and Thr residues. <ref name= "crystal"/> Full rehydration then allows the sodium ion to enter the cytoplasm. <ref name= "crystal"/> | ||
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== | |||
==Medical Implications== | ==Medical Implications== | ||
Diseases caused by mutations in sodium channels can come in many forms. Some mutations affect skeletal, cardiac or smooth muscle, while others affect neural function. Common diseases include long QT syndrome, hyperkalemic periodic paralysis, hypokalemic periodic paralysis, myotonia fluctuans and myotonia permanens among many others. <ref name ="dis">http://neuromuscular.wustl.edu/mother/chan.html#SCN4A</ref> | Diseases caused by mutations in sodium channels can come in many forms. Some mutations affect skeletal, cardiac or smooth muscle, while others affect neural function. Common diseases include long QT syndrome, hyperkalemic periodic paralysis, hypokalemic periodic paralysis, myotonia fluctuans and myotonia permanens among many others. <ref name ="dis">http://neuromuscular.wustl.edu/mother/chan.html#SCN4A</ref> | ||
=== | ===Oncology=== | ||
This disease causes seizures, fainting or sudden death from cardiac arrhythmias and is caused my a mutation in the SCN5A gene, or the gene that encodes the NaV1.5 alpha subunit. <ref name ="QT">DOI: 10.1016/0092-8674(95)90359-3</ref><ref name ="Long">http://www.mayoclinic.org/diseases-conditions/long-qt-syndrome/basics/definition/con-20025388</ref> It was found that this deletion includes residues 1505-1507 (KPQ).<ref name = "QT"/> These residues occur in the cytoplasmic linker between domain III and domain IV. <ref name = "QT"/> | This disease causes seizures, fainting or sudden death from cardiac arrhythmias and is caused my a mutation in the SCN5A gene, or the gene that encodes the NaV1.5 alpha subunit. <ref name ="QT">DOI: 10.1016/0092-8674(95)90359-3</ref><ref name ="Long">http://www.mayoclinic.org/diseases-conditions/long-qt-syndrome/basics/definition/con-20025388</ref> It was found that this deletion includes residues 1505-1507 (KPQ).<ref name = "QT"/> These residues occur in the cytoplasmic linker between domain III and domain IV. <ref name = "QT"/> | ||
=== | ===Hemolytic anemia=== | ||
Hyperkalemic period paralysis is caused by the mutations T704M, S906T, A1156T, M1360V, A1448C and/or M1592V. <ref name = "Hyper">http://neuromuscular.wustl.edu/mother/activity.html#hrpp</ref> These mutations cause periodic or permanent weakness. <ref name = "Hyper"/> Physiologically, this is a gain of function mutation. During rest after exercise, or after eating foods rich in K<sup>+</sup>, the extracellular K<sup>+</sup> increases, which mildly depolarizes the membrane.<ref name = "Hyper"/> This causes abnormal Na<sup>+</sup> channels to open, and they are unable to inactivate. <ref name = "Hyper"/> This sustained depolarization of the membrane causes even more abnormal Na<sup>+</sup> channels to open and ultimately this leads to loss of excitability and weakness. <ref name = "Hyper"/> This symptom usually appears within the first decade of life and can be aggravated by exercise, cold, potassium loading, fasting or pregnancy. <ref name = "Hyper"/> Attacks are usually brief and do not need treatment. <ref name = "Hyper"/> | Hyperkalemic period paralysis is caused by the mutations T704M, S906T, A1156T, M1360V, A1448C and/or M1592V. <ref name = "Hyper">http://neuromuscular.wustl.edu/mother/activity.html#hrpp</ref> These mutations cause periodic or permanent weakness. <ref name = "Hyper"/> Physiologically, this is a gain of function mutation. During rest after exercise, or after eating foods rich in K<sup>+</sup>, the extracellular K<sup>+</sup> increases, which mildly depolarizes the membrane.<ref name = "Hyper"/> This causes abnormal Na<sup>+</sup> channels to open, and they are unable to inactivate. <ref name = "Hyper"/> This sustained depolarization of the membrane causes even more abnormal Na<sup>+</sup> channels to open and ultimately this leads to loss of excitability and weakness. <ref name = "Hyper"/> This symptom usually appears within the first decade of life and can be aggravated by exercise, cold, potassium loading, fasting or pregnancy. <ref name = "Hyper"/> Attacks are usually brief and do not need treatment. <ref name = "Hyper"/> | ||
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Hypokalemic periodic paralysis is caused by the mutations R669H, R672H, R672G, R672S, R1132Q, and/or P1158S in the S4 segment of the NaV1.4 sodium channel. <ref name = "Hypo">http://neuromuscular.wustl.edu/mtime/mepisodic.html#hopp</ref> This disease is caused by a loss of function mutation resulting in attacks of muscular weakness. <ref name = "Hypo"/> This disorder is a dominant mutation. <ref name = "Groome">DOI: 10.1093/brain/awu015</ref> Factors that trigger these episodes include meals rich in carbohydrates, rest after exercise, early morning hours, and emotional stress. <ref name = "Groome"/> Most mutations are in two the Arg residues closes to the extracellular side of the S4 segment. <ref name = "Groome"/> These mutations cause a leak current of Na+ ions inward, which is called an "omega" current. <ref name = "Groome"/> This inward current causes the K+ channels to not be effective and results in muscle weakness. <ref name = "Groome"/> | Hypokalemic periodic paralysis is caused by the mutations R669H, R672H, R672G, R672S, R1132Q, and/or P1158S in the S4 segment of the NaV1.4 sodium channel. <ref name = "Hypo">http://neuromuscular.wustl.edu/mtime/mepisodic.html#hopp</ref> This disease is caused by a loss of function mutation resulting in attacks of muscular weakness. <ref name = "Hypo"/> This disorder is a dominant mutation. <ref name = "Groome">DOI: 10.1093/brain/awu015</ref> Factors that trigger these episodes include meals rich in carbohydrates, rest after exercise, early morning hours, and emotional stress. <ref name = "Groome"/> Most mutations are in two the Arg residues closes to the extracellular side of the S4 segment. <ref name = "Groome"/> These mutations cause a leak current of Na+ ions inward, which is called an "omega" current. <ref name = "Groome"/> This inward current causes the K+ channels to not be effective and results in muscle weakness. <ref name = "Groome"/> | ||
==References== | ==References== | ||
<references/> | <references/> | ||
