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[[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' />
== Function ==
== Function ==
'''Hemolysin''' [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 K<sup>+</sup> ions through the hydrophilic, transmembrane portion of the beta-barrel pore[http://www.sciencedirect.com/science/article/pii/S0041010101001532].


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>
==Structure==
Hemolysins have three structural variations: alpha, beta, and gamma. These hemolysin types are comprised of di-, hepta- or octomeric subunits.


[[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"/>
*Alpha-hemolysin


<Structure load='7AHL' size='350' frame='true' align='right' caption='Stapholococcal alpha-hemolysin' scene='Insert optional scene name here' />
<scene name='69/696302/Alpha-hemolysin/1'>Alpha-hemolysin</scene>
<scene name='69/696302/Beta-hemolysin/1'>TextToBeDisplayed</scene>
 
==Function==
[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>
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"/> This information was first discovered by Hodgkin and Huxley in 1952. <ref name ="physio">https://en.wikipedia.org/wiki/Hodgkin%E2%80%93Huxley_model</ref> For more information on the role of sodium channels in electrical signaling, click [https://en.wikipedia.org/wiki/Action_potential here].
 
<scene name='69/696302/Alpha-hemolysin_polar_residues/1'>Alpha-hemolysin residue polarity</scene>
 
{{Template:ColorKey_Hydrophobic}}
 
{{Template:ColorKey_Polar}}
 
*Beta-hemolysin
 
<scene name='69/696302/Beta-hemolysin/2'>Beta-hemolysin</scene>
 
Beta-hemolysins cause a total lysis of red blood cells.
 
*Gamma-hemolysin
 
<scene name='69/696302/Beta-hemolysin/1'>Gamma-hemolysin</scene>


==Structure==
[http://proteopedia.org/wiki/index.php/3b07 Gamma-hemolysin] is both hemolytic and leukotoxic.
Hemolysins have three structural variations: alpha, beta, and gamma. These hemolysin types are comprised of 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"/>
<scene name='69/696302/Beta-hemolysin/1'>Beta-hemolysin</scene>
[[Image:640px-Sodium-channel.png]]


=== Gating ===
<scene name='69/696302/Gamma-hemolysin_residue_polar/1'>Gamma-hemolysin residue polarity</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>.


===Selectivity Filter===
{{Template:ColorKey_Hydrophobic}}
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"/>


To see the selectivity filter, click <scene name='69/696300/Selectivity_pore/2'>here</scene>. T175 is blue, L176 is yellow, E177 is red and S178 is black.
{{Template:ColorKey_Polar}}


[[Image:Nature10238-f3.2.jpg]]


==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==


This image shows the crystal structure of the selectivity filter. <ref name= "crystal"/>
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>


===α Subunits===
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.


* [https://en.wikipedia.org/wiki/Nav1.1 NaV1.1]: found in central and peripheral neurons and myocytes. Click <scene name='69/696300/Nav1_1/1'>here</scene> for the structure of the NaV1.1 inactivation gate. <ref name = "sod"/>
* [https://en.wikipedia.org/wiki/Nav1.2 NaV1.2]: found in central and peripheral neurons. Click <scene name='69/696300/Nav1_2/1'>here</scene> for the structure of the NaV1.2 C terminal domain in complex with FGF13U and Ca2+/calmodulin. <ref name = "sod"/>
* [https://en.wikipedia.org/wiki/SCN3A NaV1.3]: found in central and peripheral neurons and cardiac myocytes. <ref name = "sod"/>
* [https://en.wikipedia.org/wiki/Nav1.4 NaV1.4]: found in skeletal muscle. <ref name = "sod"/>
* [https://en.wikipedia.org/wiki/Nav1.5 NaV1.5]: found in cardiac myocytes, uninnervated skeletal muscle, central neurons, gastrointestinal smooth muscle cells, and interstitial cells of Cajal. Click <scene name='69/696300/Nav1_5/1'>here</scene> for the structure of the NaV1.5 C terminal domain in complex with FGF12B and Ca2+/calmodulin. <ref name = "sod"/>
* [https://en.wikipedia.org/wiki/SCN8A NaV1.6]: found in central neurons, dorsal root ganglia, peripheral neurons, heart and glial cells. <ref name = "sod"/>
* [https://en.wikipedia.org/wiki/Nav1.7 NaV1.7]: found in dorsal root ganglia, sympathetic neurons, Schwann cells and neuroendocrine cells. <ref name = "sod"/>
* [https://en.wikipedia.org/wiki/Nav1.8 NaV1.8]: found in dorsal root ganglia. <ref name = "sod"/>
* [https://en.wikipedia.org/wiki/Nav1.9 NaV1.9]: found in dorsal root ganglia. <ref name = "sod"/>


===β Subunits===
===Pore formation===
Beta subunits function in channel gating, channel expression and form links to the cytoskeleton. <ref name = "sod"/> There are four different beta subunits named NaVβ1 through NaVβ4 and the genes are named SCN1B through SCN4B. <ref name = "sod"/>
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.


*[https://en.wikipedia.org/wiki/SCN1B NaVβ1]: Assembles with NaV1.1 and NaV1.7 and found in central and peripheral neurons, skeletal muscle, heart and glial cells. <ref name = "sod"/>
[[Image:Ncomms5897-f5.jpg]]
*[https://en.wikipedia.org/wiki/SCN2B NaVβ2]: Assembles with NaV1.1, NaV1.2, NaV1.5 and NaV1.7 and found in central and peripheral neurons, heart and glial cells. <ref name = "sod"/>
*[https://en.wikipedia.org/wiki/SCN3B NaVβ3]: Assembles with NaV1.1, NaV1.3 and NaV1.5 and found in the central and peripheral neurons, adrenal gland and heart. <ref name = "sod"/>
*[https://en.wikipedia.org/wiki/SCN4B NaVβ4]: Assembles with NaV1.1, NaV1.2, and NaV1.5 and found in the heart, skeletal muscles, central and peripheral neurons. <ref name = "sod"/>


This image shows the proposed mechanism of pore formation in the cell membrane.  <ref name ="nat"/>




==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>
===Long QT Syndrome===
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"/>


===Hyperkalemic Periodic Paralysis===
===Role in infection===
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"/>
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"/>


===Hypokalemic Periodic Paralysis===
===Oncology===
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"/>
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>


===Myotonia Fluctuans===
===Hemolytic anemia===
Myotonia fluctuans is due to the G1306A mutation in the NaV1.4 sodium channel. <ref name = "Fluct">http://neuromuscular.wustl.edu/mother/activity.html#mf</ref> All mutations at the 1306 site cause reduced channel inactivation due to the fact that the residue is located on the hinge of the channel inactivation gate. <ref name = "Fluct"/> This disease is characterized by the inability to relax voluntary muscle after vigorous exercise. However, the condition fluctuates day to day, hence the name. <ref name = "Fluct"/>  
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>  


===Myotonia Permanens===
[[Image:Hemolysis3-147A9D970590BADE656.jpg]]
Myotonia permanens is similar to myotonia fluctuans in that it causes the inability to relax voluntary muscle. <ref name = "Fluct"/> However, this disease is caused by the G1306Q mutation. <ref name = "Fluct"/> Again, this mutation causes reduced channel inactivation due to the location of the mutation on the inactivation gate. <ref name = "Fluct"/> Severe myotonia permanens may interfere with respiration and is worsened after eating K+ rich foods. <ref name = "Fluct"/>


==References==
==References==
<references/>
<references/>

Latest revision as of 16:15, 13 May 2016

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[1]. 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 [2].

Stapholococcal alpha-hemolysin

Drag the structure with the mouse to rotate


FunctionFunction

Hemolysins are most commonly proteins found in red blood cells that allow for the rapid release of small molecules and ions across the membrane. [3] or lipid biosurfactants that disrupt membrane composition resulting in cell lysis. Hemolysins act through disruption of the cell membrane. [4] 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 [5]. 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. [6]


StructureStructure

Hemolysins have three structural variations: alpha, beta, and gamma. These hemolysin types are comprised of di-, hepta- or octomeric subunits.

  • Alpha-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. [7]

Hydrophobic

Polar

  • Beta-hemolysin

Beta-hemolysins cause a total lysis of red blood cells.

  • Gamma-hemolysin

Gamma-hemolysin is both hemolytic and leukotoxic.

Hydrophobic

Polar


Pathogenic microorganismsPathogenic microorganisms

Pore-forming toxins have been shown to closely relate to the pathogenicity of the toxin-producing organism. [8] 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. [9]

MechanismMechanism

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. [10]


Pore formationPore formation

Pore formation of hemolysins is believed to be a conserved process across subtypes. [10] 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.

This image shows the proposed mechanism of pore formation in the cell membrane. [10]


Medical ImplicationsMedical Implications

Role in infectionRole in infection

Hemolysin lysis of red blood cells is a marker for many kinds of pathogenic infection characterized by death of red blood cells. [3]

OncologyOncology

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.[11]

Hemolytic anemiaHemolytic anemia

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.[12]

ReferencesReferences

  1. ↑ http://www.uniprot.org/uniprot/P09616
  2. ↑ http://www.sciencedirect.com/science/article/pii/S0041010101001532
  3. ↑ 3.0 3.1 https://en.wikipedia.org/wiki/Hemolysin#cite_note-pmid20692229-3
  4. ↑ http://www.sciencedirect.com/science/article/pii/S0005273610002610
  5. ↑ http://www.ks.uiuc.edu/Research/hemolysin/
  6. ↑ http://www.nhlbi.nih.gov/health/health-topics/topics/ha/
  7. ↑ http://www.ks.uiuc.edu/Research/hemolysin/
  8. ↑ http://www.ncbi.nlm.nih.gov/pubmed/1930675
  9. ↑ https://en.wikipedia.org/wiki/Hemolysin
  10. ↑ 10.0 10.1 10.2 Yamashita D, Sugawara T, Takeshita M, Kaneko J, Kamio Y, Tanaka I, Tanaka Y, Yao M. Molecular basis of transmembrane beta-barrel formation of staphylococcal pore-forming toxins. Nat Commun. 2014 Sep 29;5:4897. doi: 10.1038/ncomms5897. PMID:25263813 doi:http://dx.doi.org/10.1038/ncomms5897
  11. ↑ http://www.sciencedirect.com/science/article/pii/S030441651200116X
  12. ↑ https://www.nhlbi.nih.gov/health/health-topics/topics/ha

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