tailieunhanh - Báo cáo khoa hoc : Leu138 in bovine prion peptide fibrils is involved in seeding discrimination related to codon 129 M ⁄ V polymorphism in the prion peptide seeding experiment

The risk of acquiring variant Creutzfeldt–Jakob disease is closely related to polymorphism at codon 129 of the human prion gene, because almost all variant Creutzfeldt–Jakob disease patients are Met⁄Met homozygotes. Although animal transmission experiments corroborated this seeding dis-crimination, the origin of the differential seeding efficiency of the bovine prion seed for human codon 129 polymorphism remained elusive. | IFEBS Journal Leu138 in bovine prion peptide fibrils is involved in seeding discrimination related to codon 129 M V polymorphism in the prion peptide seeding experiment Tai-Yan Liao Lily . Lee and Rita . Chen Institute of BiologicalChemistry Academia Sinica Taipei Taiwan Keywords amyloid bovine spongiform encephalopathy codon 129 species barrier vCJD Correspondence R. . Chen No. 128 Sec 2 Academia Rdoa Nankang Taipei 115 Taiwan Fax 886 2 2788 9759 Tel 886 2 2785 5696 E-mail pyc@ Received 2 June 2011 revised 19 August 2011 accepted 13 September 2011 doi The risk of acquiring variant Creutzfeldt-Jakob disease is closely related to polymorphism at codon 129 of the human prion gene because almost all variant Creutzfeldt-Jakob disease patients are Met Met homozygotes. Although animal transmission experiments corroborated this seeding discrimination the origin of the differential seeding efficiency of the bovine prion seed for human codon 129 polymorphism remained elusive. Here we used a short prion protein PrP peptide as a model system to test whether seeding discrimination can be found in this simple system. We used a previously developed seed-titration method and time-resolved CD spectroscopy to compare sequence-dependent seeding efficiency regarding codon 129 polymorphism. Our results showed that the Met fi Val substitution on the human PrP huPrP peptide decreased seeding efficiency by 10 times when fibrils formed from bovine PrP bPrP peptide were used as the seed. To explore whether the different seeding barrier is due to the chemical and structural properties of Met and Val or whether another residue is involved in this peptide model we constructed three bPrP mutants V112M L138I and N143S in each of which one residue was replaced by the corresponding human residue. Our data showed that Leu138 in the bPrP seed might be the key residue causing the different seeding efficiencies related to V .