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J Biol Chem. 2014 Apr 11;289(15):10660-7. doi: 10.1074/jbc.M114.549030. Epub 2014 Mar 4.

A proposed mechanism for the promotion of prion conversion involving a strictly conserved tyrosine residue in the β2-α2 loop of PrPC.

Author information

1
From the Departments of Pathology and Medicine, University of California San Diego, La Jolla, California 92093.

Abstract

The transmission of infectious prions into different host species requires compatible prion protein (PrP) primary structures, and even one heterologous residue at a pivotal position can block prion infection. Mapping the key amino acid positions that govern cross-species prion conversion has not yet been possible, although certain residue positions have been identified as restrictive, including residues in the β2-α2 loop region of PrP. To further define how β2-α2 residues impact conversion, we investigated residue substitutions in PrP(C) using an in vitro prion conversion assay. Within the β2-α2 loop, a tyrosine residue at position 169 is strictly conserved among mammals, and transgenic mice expressing mouse PrP having the Y169G, S170N, and N174T substitutions resist prion infection. To better understand the structural requirements of specific residues for conversion initiated by mouse prions, we substituted a diverse array of amino acids at position 169 of PrP. We found that the substitution of glycine, leucine, or glutamine at position 169 reduced conversion by ∼ 75%. In contrast, replacing tyrosine 169 with either of the bulky, aromatic residues, phenylalanine or tryptophan, supported efficient prion conversion. We propose a model based on a requirement for tightly interdigitating complementary amino acid side chains within specific domains of adjacent PrP molecules, known as "steric zippers," to explain these results. Collectively, these studies suggest that an aromatic residue at position 169 supports efficient prion conversion.

KEYWORDS:

Amyloid; Infectious Diseases; Neurodegenerative Diseases; Prions; Protein Aggregation; Steric Zipper; TSE; Transmissible Spongiform Encephalopathy; β2-α2 Loop

PMID:
24596090
PMCID:
PMC4036184
DOI:
10.1074/jbc.M114.549030
[Indexed for MEDLINE]
Free PMC Article
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