The roles of the conserved tyrosine in the β2-α2 loop of the prion protein

TitleThe roles of the conserved tyrosine in the β2-α2 loop of the prion protein
Publication TypeJournal Article
Year of Publication2015
AuthorsHuang D., Caflisch A.
JournalPrion
Volume9
Start Page412
Issue6
Pagination412-419
Date PublishedNov 2015
Type of ArticleResearch Article
ISSN1933-690X
KeywordsAmino Acid Sequence, Animals, Humans, Molecular Dynamics Simulation, Mutation, Prions, Protein Conformation, Protein Structure, Secondary, Protein Structure, Tertiary, Scrapie, Tyrosine
Abstract

Prions cause neurodegenerative diseases for which no cure exists. Despite decades of research activities the function of the prion protein (PrP) in mammalians is not known. Moreover, little is known on the molecular mechanisms of the self-assembly of the PrP from its monomeric state (cellular PrP, PrP(C)) to the multimeric state. The latter state includes the toxic species (scrapie PrP, PrP(Sc)) knowledge of which would facilitate the development of drugs against prion diseases. Here we analyze the role of a tyrosine residue (Y169) which is strictly conserved in mammalian PrPs. Nuclear magnetic resonance (NMR) spectroscopy studies of many mammalian PrP(C) proteins have provided evidence of a conformational equilibrium between a 3(10)-helical turn and a type I β turn conformation in the β2-α2 loop (residues 165-175). In vitro cell-free experiments of the seeded conversion of PrP(C) indicate that non-aromatic residues at position 169 reduce the formation of proteinase K-resistant PrP. Recent molecular dynamics (MD) simulations of monomeric PrP and several single-point mutants show that Y169 stabilizes the 3(10)-helical turn conformation more than single-point mutants at position 169 or residues in contact with it. In the 3(10)-helical turn conformation the hydrophobic and aggregation-prone segment 169-YSNQNNF-175 is buried and thus not-available for self-assembly. From the combined analysis of simulation and experimental results it emerges that Y169 is an aggregation gatekeeper with a twofold role. Mutations related to 3 human prion diseases are interpreted on the basis of the gatekeeper role in the monomeric state. Another potential role of the Y169 side chain is the stabilization of the ordered aggregates, i.e., reduction of frangibility of filamentous protofibrils and fibrils, which is likely to reduce the generation of toxic species.

DOI10.1080/19336896.2015.1115944
pubindex

0204

Alternate JournalPrion
PubMed ID26689486
PubMed Central IDPMC4964861
Highlight Role: 
Aggregation and Assembly