Sandbox WWC6: Difference between revisions

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Dana Emmert, Taylor Caple Jaicks

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-[[Hemolysins]] [https://en.wikipedia.org/wiki/Hemolysin#.CE.B1-hemolysin]  are a  lipid or protein toxins secreted by pathogens that lyse erythrocyte and some bacterial cell membranes.  These toxins belong to a family of microbial exotoxins called cytolysins, which act on a broad number of cells[http://www.uniprot.org/uniprot/P09616]. The primary function of peptide hemolysins is pore formation at the cell membranes creating acytolytic effect, and is achieved by the release of cytosolic ions and small molecules through the hydrophilic, transmembrane portion of the beta-barrel pore[http://www.sciencedirect.com/science/article/pii/S0041010101001532].
+[[Hemolysins]]  are a  lipid or protein toxins secreted by pathogens that lyse erythrocyte and some bacterial cell membranes.  These toxins belong to a family of microbial exotoxins called cytolysins, which act on a broad number of cells<ref name ="cyt">http://www.uniprot.org/uniprot/P09616</ref>. The primary function of peptide hemolysins is pore formation at the cell membranes creating acytolytic effect, and is achieved by the release of cytosolic ions and small molecules through the hydrophilic, transmembrane portion of the beta-barrel pore <ref name ="bar>http://www.sciencedirect.com/science/article/pii/S0041010101001532</ref>.
 <Structure load='7AHL' size='350' frame='true' align='right' caption='Stapholococcal alpha-hemolysin' scene='Insert optional scene name here' />
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 == Function ==
+Hemolysins are most commonly proteins found in red blood cells that allow for the rapid release of small molecules and ions across the membrane. <ref name ="hem">https://en.wikipedia.org/wiki/Hemolysin#cite_note-pmid20692229-3</ref> or lipid biosurfactants that disrupt membrane composition resulting in cell lysis.  Hemolysins act through disruption of the cell membrane. <ref>http://www.sciencedirect.com/science/article/pii/S0005273610002610</ref> Pore formation is the olgomerization of the pore sunbunits within the membrane. The pore is quickly filled with water, ions, and small molecules that rapidly exit the cell, dissipating ionic gradients and membrane potential.  Osmotic pressure causes a rapid swelling of the cell, leading to total rupture of the membrane <ref name ="ion>http://www.ks.uiuc.edu/Research/hemolysin/</ref>.  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>
-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>
-Hemolysins act through disruption of the cell membrane.  Two main functions destroy phospholipid membranes: pore formation and phosphilipid hydrosysis. <ref>http://www.sciencedirect.com/science/article/pii/S0005273610002610</ref> Pore formation, the most common mechanism of hemolysin cell <ref name ="sod"/> is the olgomerization of the pore sunbunits within the membrane. The pore is quickly filled with water, ions, and small molecules that rapidly exit the cell, dissipating ionic gradients and membrane potential.  Osmotic pressure causes a rapid swelling of the cell, leading to total rupture of the membrane <ref>http://www.ks.uiuc.edu/Research/hemolysin/<ref>.
 ==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.
+*Alpha-hemolysin
-===Alpha-hemolysin===
+<scene name='69/696302/Alpha-hemolysin/1'>Alpha-hemolysin</scene>
-<scene name='69/696302/Alpha-hemolysin/1'>Alpha-hemolysin</scene>
+[http://proteopedia.org/wiki/index.php/Pore_forming_toxin,_%CE%B1-hemolysin Alpha hemolysin] causes a partial lysis of red blood cells.  The heptameric pore assembles from water-soluble subunits.  The alpha subunit, depicted right, consists seven identical monomeric units that exhibit rotational symmetry in oligomerized form.  Each distinct subunit is differently colored for easy identification.  The beta-barrel transmembrane domain is 50 Å in length. <ref>http://www.ks.uiuc.edu/Research/hemolysin/</ref>
-Alpha hemolysins cause a partial lysis of red blood cells.
+<scene name='69/696302/Alpha-hemolysin_polar_residues/1'>Alpha-hemolysin residue polarity</scene>
-The heptameric pore assembles from water-soluble subunits  The transmembrane domain of this water-filled pore is primarily comprised of an anti-parallel beta-barrel
+{{Template:ColorKey_Hydrophobic}}
+{{Template:ColorKey_Polar}}
-===Beta-hemolysin===
+*Beta-hemolysin
 <scene name='69/696302/Beta-hemolysin/2'>Beta-hemolysin</scene>
@@ Line 31: / Line 30: @@
 Beta-hemolysins cause a total lysis of red blood cells.
+*Gamma-hemolysin
-===Gamma-hemolysin===
 <scene name='69/696302/Beta-hemolysin/1'>Gamma-hemolysin</scene>
+[http://proteopedia.org/wiki/index.php/3b07 Gamma-hemolysin] is both hemolytic and leukotoxic.
-Gamma-hemolysin is both hemolytic and leukotoxic.
+<scene name='69/696302/Gamma-hemolysin_residue_polar/1'>Gamma-hemolysin residue polarity</scene>
-==Pathogenic Microorganisms==
+{{Template:ColorKey_Hydrophobic}}
-Pore-forming toxins have been shown to closely relate to the pathogenicity of the toxin-producing organism <ref>http://www.ncbi.nlm.nih.gov/pubmed/1930675<ref> Both gram positive and gram negative bacteria are producers of hemolysins, as well as some clinically relevant fungi.  Toxin secretion facillitates the availability of water, ions, and small molecules like sugar for the secreting pathogen.
+{{Template:ColorKey_Polar}}
-== Mechanism of action ==
-Four of each of the two subunits assemble in an alternating, circular pattern in the γ-HL pore, whereas seven distinct α-HL protomers assemble in a circular arrangement in the α-HL pore. These typically are comprised of three domains: the cap, rim and stem domains, named for the structural resemblance to a mushroom. The cap domain contains β-sandwiches from each protomer, while just below, the rim domain contains four looping β-strands. The stem domain takes on the antiparallel β-barrel, a portion of which becomes the transmembrane structure.
+==Pathogenic microorganisms==
+Pore-forming toxins have been shown to closely relate to the pathogenicity of the toxin-producing organism. <ref>http://www.ncbi.nlm.nih.gov/pubmed/1930675</ref> Both gram positive and gram negative bacteria are producers of hemolysins, as well as some clinically relevant fungi.  Toxin secretion facillitates the availability of water, ions, and small molecules like sugar for the secreting pathogen. Hemolysin producing pathogen are identified by their ability to lyse cells in vitro. <ref>https://en.wikipedia.org/wiki/Hemolysin</ref>
+==Mechanism==
+Four of each of the two subunits assemble in an alternating, circular pattern in the γ-HL pore, whereas seven distinct α-HL protomers assemble in a circular arrangement in the α-HL pore. These typically are comprised of three domains: the cap, rim and stem domains, named for the structural resemblance to a mushroom. The cap domain contains β-sandwiches from each protomer, while just below, the rim domain contains four looping β-strands. The stem domain takes on the antiparallel β-barrel, a portion of which becomes the transmembrane structure. <ref name ="nat">doi:10.1038/ncomms5897</ref>
 ===Pore formation===
+Pore formation of hemolysins is believed to be a conserved process across subtypes. <ref name ="nat"/>
 Studies suggest that pore formation is achieved through a nonlytic intermediate oligomer, known as a prepore.  The prepore model proposal suggests that the monomeric components assemble on the cell membrane surfacte into a prepore with prestem subunits packed inside. The formed prepore then goes through a conformational change prestem, forming the β-barrel pore. Several issues with the proposed pore formation mechanism have been identified including steric hindrance of the packed prestem structure.
 [[Image:Ncomms5897-f5.jpg]]
-This image shows the proposed mechanism of pore formation in the cell membrane.  <ref>http://www.nature.com/ncomms/2014/140929/ncomms5897/full/ncomms5897.html<ref>
+This image shows the proposed mechanism of pore formation in the cell membrane.  <ref name ="nat"/>
+==Medical Implications==
 ===Role in infection===
-There are nine different α subunits named NaV1.1 through NAV1.9. <ref name = "sod"/> Genes are SCN1 through SCN11. <ref name = "sod"/> These structures differ in their sequence and kinetics. <ref name = "sod"/> As stated above, the α subunit is necessary to the function of the channel and can function independently of the β subunit. You can find the structures and more information below.
+Hemolysin lysis of red blood cells is a marker for many kinds of pathogenic infection characterized by death of red blood cells. <ref name="hem"/>
-==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>
 ===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"/>
+Thermostable direct hemoslysin (TDH) is one type of hemolysin, secreted by ''Vibrio parahaemolyticus'', that may be linked to the down regulation of colon carcinoma cell proliferation.  The presence of this hemolysin is responsible for the influx of calcium ions from the extracellular space, activating protein kinase C, an inhibitor of tyrosine kinase activity on a key growth factor of this cancer.<ref>http://www.sciencedirect.com/science/article/pii/S030441651200116X</ref>
 ===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"/>
+Hemolytic anemia occurs when lysis of red blood cells occurs at rates faster than they can be replaced by bone marrow. Hypoxia due to this condition can result in dizziness, shortness of breath, poor maintenance of body temperature, and jaundice.<ref>https://www.nhlbi.nih.gov/health/health-topics/topics/ha</ref>
-===Marker for fungi exposure===
-Many indoor fungi have been shown to produse both alpha and beta-hemolysins.  The treatment of blood samples with
 [[Image:Hemolysis3-147A9D970590BADE656.jpg]]
-===Treatment===
 ==References==
 <references/>