Human Prion Protein Dimer: Difference between revisions
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<StructureSection load='1qlx' size='450' side='right' caption='Human prion protein (PDB code [[1qlx]])' scene=''> | |||
== Prions as a disease causing agent== | == Prions as a disease causing agent== | ||
[[Image:1i4m.png| | [[Image:1i4m.png|left|150px|thumb|Human Prion Protein in dimer form [[1i4m]]]] | ||
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[[Image:10131_lores.jpg|left|300px|thumb|Pictomicrograph of Creutzfeldt-Jakob positive brain tissue|Caption: Holes in this sponge like brain tissue result from pockets of prion aggregation <ref>[http://phil.cdc.gov/PHIL_Images/10131/10131_lores.jpg Image of Creutzfeldt-Jakob positive brain tissue] was obtained from The CDC's Public Health Image Library.</ref>]] | |||
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[http://en.wikipedia.org/wiki/Prion Prions] are infectious or genetically coded misfolded proteins which act as templates upon which properly folded prion protein monomers can aggregate. Prions contain no nucleic acid such as other infectoius molecules or organisms. Human Prion Protein or Major Prion protein, exists as a normal constituent of human cells, found mostly in the brain<ref>Centers for Disease Control and Prevention: Prions. http://www.cdc.gov/ncidod/dvrd/prions/</ref> and is called PrP<sup>C</sup>.<ref name="Prusiner">PMID:9811807</ref> PrP<sup>C</sup> is composed of mostly helix whereas the infectious form, PrP<sup>Sc</sup> (also known as "scrapie" form), is composed of high percentage beta sheets.<ref name="Prusiner">PMID:9811807</ref> | [http://en.wikipedia.org/wiki/Prion Prions] are infectious or genetically coded misfolded proteins which act as templates upon which properly folded prion protein monomers can aggregate. Prions contain no nucleic acid such as other infectoius molecules or organisms. Human Prion Protein or Major Prion protein, exists as a normal constituent of human cells, found mostly in the brain<ref>Centers for Disease Control and Prevention: Prions. http://www.cdc.gov/ncidod/dvrd/prions/</ref> and is called PrP<sup>C</sup>.<ref name="Prusiner">PMID:9811807</ref> PrP<sup>C</sup> is composed of mostly helix whereas the infectious form, PrP<sup>Sc</sup> (also known as "scrapie" form), is composed of high percentage beta sheets.<ref name="Prusiner">PMID:9811807</ref> | ||
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== Unfolding Mechanism == | == Unfolding Mechanism == | ||
Currently, the mechanism by which a template prion unfolds | Currently, the mechanism by which a template prion unfolds the helices of a properly folded prion protein is unknown. Specific residues have been shown to either confer resistance or lend themselves to this unfolding. | ||
===PrP<sup>C</sup> natural monomer=== | ===PrP<sup>C</sup> natural monomer=== | ||
This monomeric structure is the form of Major Prion Protein as it appears in a non-diseased individual. The majority of this 3D structure is <scene name='User:Erin_May/Sandbox_1/Alpha_helices/1'>alpha helices</scene> and two small beta sheets. | This monomeric structure is the form of Major Prion Protein as it appears in a non-diseased individual. The majority of this 3D structure is <scene name='User:Erin_May/Sandbox_1/Alpha_helices/1'>alpha helices</scene> and two small beta sheets. | ||
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The following residue alterations confer increased susceptibility to the unfolding of these alpha helices characteristic of spongiform encephalopathies. | The following residue alterations confer increased susceptibility to the unfolding of these alpha helices characteristic of spongiform encephalopathies. | ||
Residue 129 Val-->Met confers increased susceptibility to contracting spongiform encephalopathies. The alteration from 129 valine to 129 methionine does not majorly change electrostatics as both are hydrophobic. The methionine group is bulkier however. Due to the limitations of viewing the monomeric form, <scene name='User:Erin_May/Sandbox_1/Methionine_129/1'>Methionine 129</scene>, does not offer a possible mechanism of unfolding or aggregation. This single residue, however has incredible actions. As of January 2010, only individuals with homozygous Metionine 129 had been diagnosed with infectious Creutzfeldt–Jakob disease.<ref name="Lee">PMID:19927125</ref> | Residue 129 Val-->Met confers increased susceptibility to contracting spongiform encephalopathies. The alteration from 129 valine to 129 methionine does not majorly change electrostatics as both are hydrophobic. The methionine group is bulkier however. Due to the limitations of viewing the monomeric form, <scene name='User:Erin_May/Sandbox_1/Methionine_129/1'>Methionine 129</scene>, it does not offer a possible mechanism of unfolding or aggregation. This single residue, however has incredible actions. As of January 2010, only individuals with homozygous Metionine 129 had been diagnosed with infectious Creutzfeldt–Jakob disease.<ref name="Lee">PMID:19927125</ref> | ||
<scene name='User:Erin_May/Sandbox_1/Species_variable_domain/1'>Residues 164 to 170</scene> exhibit species specific residues. This region is most variable between species. Residue shifts in this section increase or decrease susceptibility from inter-species transmission of TSE's. The more similar this region is between species, the more likely each are able to transfer infectious prions between the two.<ref name="Lee">PMID:19927125</ref> | <scene name='User:Erin_May/Sandbox_1/Species_variable_domain/1'>Residues 164 to 170</scene> exhibit species specific residues. This region is most variable between species. Residue shifts in this section increase or decrease susceptibility from inter-species transmission of TSE's. The more similar this region is between species, the more likely each are able to transfer infectious prions between the two.<ref name="Lee">PMID:19927125</ref> | ||
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[[Image:F4.large.jpg| | [[Image:F4.large.jpg|left|300px|thumb|Electrostatic potential alteration E200K|Caption: This shows (a&c) the electrostatic potential of wild-type Human Prion Protein with Glu200 and (b&d) the electrostatic potential of variant Lys200. <ref name="Zhang">PMID:10954699</ref>]] | ||
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=== PrP<sup>Sc</sup> === | === PrP<sup>Sc</sup> === | ||
The majority of this structure is <scene name='User:Erin_May/Sandbox_1/Beta_sheets/1'>beta sheets</scene>. | The majority of this structure is <scene name='User:Erin_May/Sandbox_1/Beta_sheets/1'>beta sheets</scene>. | ||
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The Cystine residues which were formerly part of disulfide bonds have been reduced catalytically without any chemical reducing agent. <ref name="Knaus">PMID:11524679</ref> | The Cystine residues which were formerly part of disulfide bonds have been reduced catalytically without any chemical reducing agent. <ref name="Knaus">PMID:11524679</ref> | ||
===Dimer Form=== | ===Dimer Form=== | ||
< | <scene name='Human_Prion_Protein_Dimer/Cv/1'>Major Prion Protein: Dimerized</scene> [[1i4m]]. | ||
The <scene name='User:Erin_May/Sandbox_1/Previously_shown_residues/1'>residues</scene>, shown above, alter the function of Major Prion Protein's ability to re-fold, however their positions on the wild-type monomer and fully unfolded PrP<sup>Sc</sup>, do not illustrate a clear mechanism for propagation. The dimer brings light to these residues influence on the infectious qualities of | The <scene name='User:Erin_May/Sandbox_1/Previously_shown_residues/1'>residues</scene>, shown above, alter the function of Major Prion Protein's ability to re-fold, however their positions on the wild-type monomer and fully unfolded PrP<sup>Sc</sup>, do not illustrate a clear mechanism for propagation. The dimer brings light to these residues' influence on the infectious qualities of PrP<sup>Sc</sup>. | ||
It is theorized from this dimeric structure that the dimerization is the first step in amyloid formation and the presence of these dimers could possibly speed up the aggregation of PrP<sup>Sc</sup>. | It is theorized from this dimeric structure that the dimerization is the first step in amyloid formation and the presence of these dimers could possibly speed up the aggregation of PrP<sup>Sc</sup>. | ||
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The following interactions and residue switching portray possible catalytic sites: | The following interactions and residue switching portray possible catalytic sites: | ||
Residues 129 | Residues 129, and 164 to 170 are shown to exist right at the dimer interfaces and residue 200 exists at the switch region. The location of these residues within the dimer indicates that their key operation is found somewhere in the dimerization process. <ref name="Lee">PMID:19927125</ref><ref name="Knaus">PMID:11524679</ref><ref name="Zhang">PMID:10954699</ref> | ||
Helix 1 (Ser 143−Tyr 157) exists at the <scene name='User:Erin_May/Sandbox_1/Nonpolar_at_dimer_interface/2'>dimer interface</scene>. Many nonpolar residues form Van der Waals attractions. Acidic and mostly negative residues are shown in blue. Basic and mostly positive residues are shown in red. The interactions between these also stabilize the dimer interface. | Helix 1 (Ser 143−Tyr 157) exists at the <scene name='User:Erin_May/Sandbox_1/Nonpolar_at_dimer_interface/2'>dimer interface</scene>. Many nonpolar residues form Van der Waals attractions. Acidic and mostly negative residues are shown in blue. Basic and mostly positive residues are shown in red. The interactions between these also stabilize the dimer interface. | ||