title: The protonation state of histidine 111 regulates the aggregation of the evolutionary most conserved region of the human prion protein.
abstract: In a group of neurodegenerative diseases, collectively termed transmissible spongiform encephalopathies, the prion protein aggregates into β-sheet rich amyloid-like deposits. Because amyloid structure has been connected to different prion strains and cellular toxicity, it is important to obtain insight into the structural properties of prion fibrils. Using a combination of solution NMR spectroscopy, thioflavin-T fluorescence and electron microscopy we here show that within amyloid fibrils of a peptide containing residues 108-143 of the human prion protein [humPrP (108-143)]-the evolutionary most conserved part of the prion protein - residue H111 and S135 are in close spatial proximity and their interaction is critical for fibrillization. We further show that residues H111 and H140 share the same microenvironment in the unfolded, monomeric state of the peptide, but not in the fibrillar form. While protonation of H140 has little influence on fibrillization of humPrP (108-143), a positive charge at position 111 blocks the conformational change, which is necessary for amyloid formation of humPrP (108-143). Our study thus highlights the importance of protonation of histidine residues for protein aggregation and suggests point mutations to probe the structure of infectious prion particles.
authors.affiliation: Department for NMR-Based Structural Biology, Max Planck Institute for Biophysical Chemistry, Am Fassberg 11, Göttingen, 37077, Germany.
authors.forename: Luis
authors.initials: L
authors.lastname: Fonseca-Ornelas
authors.affiliation: Department for NMR-Based Structural Biology, Max Planck Institute for Biophysical Chemistry, Am Fassberg 11, Göttingen, 37077, Germany.|German Center for Neurodegenerative Diseases (DZNE), Von Siebold-Str. 3a, Göttingen, 37075, Germany.|Department of Neurology, University Medical Center Göttingen, University of Göttingen, Am Waldweg 33, Göttingen, 37073, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Zweckstetter
mesh_terms: D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D058227:Amyloidogenic Proteins / Q000737:chemistry*; D017124:Conserved Sequence; D019143:Evolution, Molecular; D006639:Histidine / Q000737:chemistry*; D006801:Humans; D009154:Mutation; D010455:Peptides / Q000737:chemistry*; D000072002:Prion Proteins / Q000737:chemistry*; D066329:Protein Aggregates; D000072417:Protein Domains; D017510:Protein Folding; D017433:Protein Structure, Secondary; D011522:Protons; D012694:Serine / Q000737:chemistry*; D055672:Static Electricity
chemical_list: D058227:Amyloidogenic Proteins; D010455:Peptides; D000072002:Prion Proteins; D066329:Protein Aggregates; D011522:Protons; D012694:Serine; D006639:Histidine
keywords: NMR spectroscopy; amyloid; misfolding; prion protein