Sandbox WWC6
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].
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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
- ↑ http://www.uniprot.org/uniprot/P09616
- ↑ http://www.sciencedirect.com/science/article/pii/S0041010101001532
- ↑ 3.0 3.1 https://en.wikipedia.org/wiki/Hemolysin#cite_note-pmid20692229-3
- ↑ http://www.sciencedirect.com/science/article/pii/S0005273610002610
- ↑ http://www.ks.uiuc.edu/Research/hemolysin/
- ↑ http://www.nhlbi.nih.gov/health/health-topics/topics/ha/
- ↑ http://www.ks.uiuc.edu/Research/hemolysin/
- ↑ http://www.ncbi.nlm.nih.gov/pubmed/1930675
- ↑ https://en.wikipedia.org/wiki/Hemolysin
- ↑ 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
- ↑ http://www.sciencedirect.com/science/article/pii/S030441651200116X
- ↑ https://www.nhlbi.nih.gov/health/health-topics/topics/ha