Prion

Function

Prion (PrP) is a protein which becomes infectious upon undergoing conformation change to an amyloid form, which is self-propagating and becomes resistant to protease degradation. The fungus Podospora anserine has a prion-like protein HET-S which undergoes a conformation change to amyloid form which prevents its colony from merging with non-compatible colonies. Yeast prion proteins are Sup35 and Ure2. For more details see

• Prion protein
  
• Human Prion Protein Dimer
  
• Doppel
  
• Group:SMART:A Physical Model of the Structure of GNNQQNY from Yeast Prion Sup35
  

Click here to see (morph was taken from Gallery of Morphs of the Yale Morph Server).

Dominant-negative Effects in Prion Diseases: Insights from Molecular Dynamics Simulations on ^[1]

The key event in prion diseases is the conformational conversion from the cellular form of the 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 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”. (colored in yellow) in in vivo or in in vitro cell-culture experiments, the (in darkmagenta). Our main results are the following: (i) The chimeras resistant to PrP^Sc infection show between the α1 helix and N-terminal of α3 helix than HuPrP, MoPrP and the non-resistant chimeras (). This is due to stronger specific interactions between these two regions, mainly the and the . (ii) The β2-α2 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 Mo-like pattern (colored in green), 3₁₀-helix conformation is stabilized by the . In the Hu-like pattern (colored in darkred), a 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 β2-α2 loop. This suggests that the compatible loop conformation allows these dominant-negative chimeras to interfere with the conversion of MoPrP to PrP^Sc. The structural features presented here indicate that stronger interactions between α1 helix and N-terminal of α3 helix are related to the resistance to PrP^C → PrP^Sc conversion, while the β2-α2 loop conformation may play an important role in the dominant-negative effect.

3D structures of prion

Prion 3D structures