Prion: Difference between revisions

==  Dominant-negative Effects in Prion Diseases==

The key event in prion diseases is the conformational conversion from the cellular form of the [[Prion_protein|prion protein]] (PrP^C) to its pathogenic scrapie form PrP^Sc (or prion). PrP^Sc is the sole causative agent of prion diseases which self-propagates by converting PrP^C to nascent PrP^Sc. Mutations in the open reading sequence of the [[Prion_protein|prion protein]] gene can introduce changes in the protein structure and alter PrP^Sc formation and propagation, possibly by (de)stabilizing the physiological folding of PrP^C and/or affecting its interactions with some yet unknown cellular factors. Some PrP polymorphisms may even inhibit the wild-type (WT) PrP^C from being converted to PrP^Sc, with the so-called “dominant-negative” effect.  

Here we use molecular dynamics simulations to investigate the structural determinants of the globular domain in engineered Mouse (Mo) PrP variants, in WT human (Hu) PrP (PDB: [[1hjn]]) and in WT MoPrP (PDB: [[1xyx]]). The Mo PrP variants investigated here contain one or two residues from ''Homo sapiens'' and are denoted “MoPrP chimeras”. <scene name='Journal:JBSD:4/Cv/3'>Some of them are resistant to PrP^Sc infection</scene> <span style="color:yellow;background-color:black;font-weight:bold;">(colored in yellow)</span> in ''in vivo'' or in ''in vitro'' cell-culture experiments, the <scene name='Journal:JBSD:4/Cv/7'>others are not</scene> <font color='darkmagenta'><b>(in darkmagenta)</b></font>. Our main results are the following: (i) The chimeras resistant to PrP^Sc infection show <scene name='Journal:JBSD:4/Cv/8'>shorter intramolecular distances</scene> between the &#945;1 helix and N-terminal of &#945;3 helix than HuPrP, MoPrP and the non-resistant chimeras (<scene name='Journal:JBSD:4/Cv/12'>click here to see morph</scene>). This is due to stronger specific interactions between these two regions, mainly the <scene name='Journal:JBSD:4/Cv/9'>Y149-D202 and D202-Y157 (in Hu numbering and hereafter) hydrogen bonds</scene> and the <scene name='Journal:JBSD:4/Cv/10'>R156-E196 salt bridge</scene>. (ii) The &#946;2-&#945;2 <scene name='Journal:JBSD:4/Cv1/2'>loop (residues 167-171)</scene> of PrP^C is known to differ in its conformation across different species and is suggested to be responsible for the species barrier of PrP^Sc propagation. Our simulations detect exchanges between different conformations in this loop which can be categorized into two distinct patterns: some chimeras experience a 3₁₀-helix/turn pattern like in MoPrP and others show a bend/turn pattern like in HuPrP. In the <span style="color:lime;background-color:black;font-weight:bold;">Mo-like pattern (colored in green)</span>, 3₁₀-helix conformation is stabilized by the <scene name='Journal:JBSD:4/Cv1/3'>Q168-P165 and Y169-V166 hydrogen bonds</scene>. In the <font color='darkred'><b>Hu-like pattern (colored in darkred)</b></font>, a <scene name='Journal:JBSD:4/Cv1/4'>D167-S170 hydrogen bond</scene> stabilizes the bend conformation. Interestingly, the dominant-negative effect of MoPrP chimeras over WT MoPrP occurs if the chimera not only resists PrP^Sc infection but also adopts the Mo-like pattern of exchanges between conformations in the &#946;2-&#945;2 loop. This suggests that the compatible loop conformation allows these dominant-negative chimeras to interfere with the conversion of MoPrP to PrP^Sc.