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Sandbox WWC6

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FunctionFunction

Hemolysin [1] 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[2]. 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+ ions through the hydrophilic, transmembrane portion of the beta-barrel pore[3].


Hemolysins are most commonly proteins found in red blood cells that selectively allow for the diffusion of potassium ions across the membrane. [1] 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.[2] 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. [3] [4] The alpha subunit is able to function independently of the beta subunit. [3]

Stapholococcal alpha-hemolysin

Drag the structure with the mouse to rotate

FunctionFunction

Hemolysins act through disruption of the cell membrane. Two main functions destroy phospholipid membranes: pore formation and phosphilipid hydrosysis. [5] Pore formation, the most common mechanism of hemolysin cell [4] This information was first discovered by Hodgkin and Huxley in 1952. [6] For more information on the role of sodium channels in electrical signaling, click here.

StructureStructure

Hemolysins have three structural variations: alpha, beta, and gamma. These hemolysin types are comprised of hepta or octomeric subunits.[4] The alpha subunit, depicted right, consists of four repeating structures, named I through IV and shown in different colors . [7] These structures consist of six transmembrane alpha helices named S1 through S6. [7] Interestingly, each repeating subunit resembles a bacterial K+ channel. [7] These subunits fold together to form a central pore, and this complete structure resembles a bacterial Ca2+ channel. [7]

 

GatingGating

The S1 through S4 segments make up the gating mechanism. [8] In particular, the S4 segments consist of repeated motifs of a positively charged residue (usually Arg) followed by two hydrophobic residues. [8] 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.[8] S4 segments can be seen in red . 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. [8] 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+ channel. [7] The outward movement of the S4 segment moves the S4-S5 linker, which pulls the S5-S6 segments and opens the pore. [8] Overall, the voltage sensing domain makes a rolling motion of the S4-S5 linker around the pore. [8] The S4-S5 linker can be seen .

Selectivity FilterSelectivity Filter

This channel conducts sodium at nearly the rate of free diffusion. [8] This pore consists of an outer funnel-like vestibule, a selectivity filter, a central cavity, and an intracellular activation gate. [8] Unlike the K+ channel, the Na+ channel conducts sodium ions that are hydrated with four water molecules. [8] 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. [7] It is likely that the sodium ion can get much closer to the channel entry than a larger K+ 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 [8]. The pore is made up of T175, L176, E177 and S178. [8] The Glu side chains act as hydrogen bond acceptors two in-plane molecules surrounding the sodium ion. [8] The other two water molecules would be axial to the sodium ion. [8] Full rehydration would occur when the ion moves next to the Leu and Thr residues. [8] Full rehydration then allows the sodium ion to enter the cytoplasm. [8]

To see the selectivity filter, click . T175 is blue, L176 is yellow, E177 is red and S178 is black.

 


This image shows the crystal structure of the selectivity filter. [8]

α Subunitsα Subunits

There are nine different α subunits named NaV1.1 through NAV1.9. [4] Genes are SCN1 through SCN11. [4] These structures differ in their sequence and kinetics. [4] 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.

  • NaV1.1: found in central and peripheral neurons and myocytes. Click for the structure of the NaV1.1 inactivation gate. [4]
  • NaV1.2: found in central and peripheral neurons. Click for the structure of the NaV1.2 C terminal domain in complex with FGF13U and Ca2+/calmodulin. [4]
  • NaV1.3: found in central and peripheral neurons and cardiac myocytes. [4]
  • NaV1.4: found in skeletal muscle. [4]
  • NaV1.5: found in cardiac myocytes, uninnervated skeletal muscle, central neurons, gastrointestinal smooth muscle cells, and interstitial cells of Cajal. Click for the structure of the NaV1.5 C terminal domain in complex with FGF12B and Ca2+/calmodulin. [4]
  • NaV1.6: found in central neurons, dorsal root ganglia, peripheral neurons, heart and glial cells. [4]
  • NaV1.7: found in dorsal root ganglia, sympathetic neurons, Schwann cells and neuroendocrine cells. [4]
  • NaV1.8: found in dorsal root ganglia. [4]
  • NaV1.9: found in dorsal root ganglia. [4]

β Subunitsβ Subunits

Beta subunits function in channel gating, channel expression and form links to the cytoskeleton. [4] There are four different beta subunits named NaVβ1 through NaVβ4 and the genes are named SCN1B through SCN4B. [4]

  • NaVβ1: Assembles with NaV1.1 and NaV1.7 and found in central and peripheral neurons, skeletal muscle, heart and glial cells. [4]
  • NaVβ2: Assembles with NaV1.1, NaV1.2, NaV1.5 and NaV1.7 and found in central and peripheral neurons, heart and glial cells. [4]
  • NaVβ3: Assembles with NaV1.1, NaV1.3 and NaV1.5 and found in the central and peripheral neurons, adrenal gland and heart. [4]
  • NaVβ4: Assembles with NaV1.1, NaV1.2, and NaV1.5 and found in the heart, skeletal muscles, central and peripheral neurons. [4]


Medical ImplicationsMedical 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. [9]

Long QT SyndromeLong 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. [10][11] It was found that this deletion includes residues 1505-1507 (KPQ).[10] These residues occur in the cytoplasmic linker between domain III and domain IV. [10]

Hyperkalemic Periodic ParalysisHyperkalemic Periodic Paralysis

Hyperkalemic period paralysis is caused by the mutations T704M, S906T, A1156T, M1360V, A1448C and/or M1592V. [12] These mutations cause periodic or permanent weakness. [12] Physiologically, this is a gain of function mutation. During rest after exercise, or after eating foods rich in K+, the extracellular K+ increases, which mildly depolarizes the membrane.[12] This causes abnormal Na+ channels to open, and they are unable to inactivate. [12] This sustained depolarization of the membrane causes even more abnormal Na+ channels to open and ultimately this leads to loss of excitability and weakness. [12] This symptom usually appears within the first decade of life and can be aggravated by exercise, cold, potassium loading, fasting or pregnancy. [12] Attacks are usually brief and do not need treatment. [12]

Hypokalemic Periodic ParalysisHypokalemic Periodic Paralysis

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. [13] This disease is caused by a loss of function mutation resulting in attacks of muscular weakness. [13] This disorder is a dominant mutation. [14] Factors that trigger these episodes include meals rich in carbohydrates, rest after exercise, early morning hours, and emotional stress. [14] Most mutations are in two the Arg residues closes to the extracellular side of the S4 segment. [14] These mutations cause a leak current of Na+ ions inward, which is called an "omega" current. [14] This inward current causes the K+ channels to not be effective and results in muscle weakness. [14]

Myotonia FluctuansMyotonia Fluctuans

Myotonia fluctuans is due to the G1306A mutation in the NaV1.4 sodium channel. [15] 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. [15] This disease is characterized by the inability to relax voluntary muscle after vigorous exercise. However, the condition fluctuates day to day, hence the name. [15]

Myotonia PermanensMyotonia Permanens

Myotonia permanens is similar to myotonia fluctuans in that it causes the inability to relax voluntary muscle. [15] However, this disease is caused by the G1306Q mutation. [15] Again, this mutation causes reduced channel inactivation due to the location of the mutation on the inactivation gate. [15] Severe myotonia permanens may interfere with respiration and is worsened after eating K+ rich foods. [15]

ReferencesReferences

  1. ↑ https://en.wikipedia.org/wiki/Hemolysin#cite_note-pmid20692229-3
  2. ↑ http://www.nhlbi.nih.gov/health/health-topics/topics/ha/
  3. ↑ 3.0 3.1 Isom LL. Sodium channel beta subunits: anything but auxiliary. Neuroscientist. 2001 Feb;7(1):42-54. PMID:11486343
  4. ↑ 4.00 4.01 4.02 4.03 4.04 4.05 4.06 4.07 4.08 4.09 4.10 4.11 4.12 4.13 4.14 4.15 4.16 4.17 4.18 4.19 4.20 Cite error: Invalid <ref> tag; no text was provided for refs named sod
  5. ↑ http://www.sciencedirect.com/science/article/pii/S0005273610002610
  6. ↑ https://en.wikipedia.org/wiki/Hodgkin%E2%80%93Huxley_model
  7. ↑ 7.0 7.1 7.2 7.3 7.4 7.5 Marban E, Yamagishi T, Tomaselli GF. Structure and function of voltage-gated sodium channels. J Physiol. 1998 May 1;508 ( Pt 3):647-57. doi: 10.1111/j.1469-7793.1998.647bp.x. PMID:9518722 doi:http://dx.doi.org/10.1111/j.1469-7793.1998.647bp.x
  8. ↑ 8.00 8.01 8.02 8.03 8.04 8.05 8.06 8.07 8.08 8.09 8.10 8.11 8.12 8.13 8.14 8.15 Cite error: Invalid <ref> tag; no text was provided for refs named crystal
  9. ↑ http://neuromuscular.wustl.edu/mother/chan.html#SCN4A
  10. ↑ 10.0 10.1 10.2 DOI: 10.1016/0092-8674(95)90359-3
  11. ↑ http://www.mayoclinic.org/diseases-conditions/long-qt-syndrome/basics/definition/con-20025388
  12. ↑ 12.0 12.1 12.2 12.3 12.4 12.5 12.6 http://neuromuscular.wustl.edu/mother/activity.html#hrpp
  13. ↑ 13.0 13.1 http://neuromuscular.wustl.edu/mtime/mepisodic.html#hopp
  14. ↑ 14.0 14.1 14.2 14.3 14.4 Groome JR, Lehmann-Horn F, Fan C, Wolf M, Winston V, Merlini L, Jurkat-Rott K. NaV1.4 mutations cause hypokalaemic periodic paralysis by disrupting IIIS4 movement during recovery. Brain. 2014 Apr;137(Pt 4):998-1008. doi: 10.1093/brain/awu015. Epub 2014 Feb 18. PMID:24549961 doi:http://dx.doi.org/10.1093/brain/awu015
  15. ↑ 15.0 15.1 15.2 15.3 15.4 15.5 15.6 http://neuromuscular.wustl.edu/mother/activity.html#mf

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