A Proposed Mechanism for the Promotion of Prion Conversion Involving a Strictly Conserved Tyrosine Residue in the beta(2)-alpha (2) Loop of PrPC

作者：Kurt Timothy D; Jiang Lin; Bett Cyrus; Eisenberg David; Sigurdson Christina J^*

来源：Journal of Biological Chemistry, 2014, 289(15): 10660-10667.

DOI：10.1074/jbc.M114.549030

• Amyloid
• Infectious Diseases
• Neurodegenerative Diseases
• Prions
• Protein Aggregation
• (2)-(2) Loop
• TSE
• Steric Zipper
• Transmissible Spongiform Encephalopathy

Background: Single residue differences can block conversion of the cellular prion protein (PrP) to the pathogenic conformation. Results: Prion conversion was reduced by non-aromatic amino acids at PrP position 169 in the (2)-(2) loop. Conclusion: The conserved tyrosine side chain at PrP position 169 promotes efficient prion formation. Significance: These findings are consistent with a steric zipper model of prion conversion.
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 (2)-(2) loop region of PrP. To further define how (2)-(2) residues impact conversion, we investigated residue substitutions in PrPC using an in vitro prion conversion assay. Within the (2)-(2) 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 approximate to 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.

• 出版日期2014-4-11
• 单位UCLA