title: Prion Protein Prolines 102 and 105 and the Surrounding Lysine Cluster Impede Amyloid Formation.
abstract: Human prion diseases can have acquired, sporadic, or genetic origins, each of which results in the conversion of prion protein (PrP) to transmissible, pathological forms. The genetic prion disease Gerstmann-Straussler-Scheinker syndrome can arise from point mutations of prolines 102 or 105. However, the structural effects of these two prolines, and mutations thereof, on PrP misfolding are not well understood. Here, we provide evidence that individual mutations of Pro-102 or Pro-105 to noncyclic aliphatic residues such as the Gerstmann-Straussler-Scheinker-linked leucines can promote the in vitro formation of PrP amyloid with extended protease-resistant cores reminiscent of infectious prions. This effect was enhanced by additional charge-neutralizing mutations of four nearby lysine residues comprising the so-called central lysine cluster. Substitution of these proline and lysine residues accelerated PrP conversion such that spontaneous amyloid formation was no longer slower than scrapie-seeded amyloid formation. Thus, Pro-102 and Pro-105, as well as the lysines in the central lysine cluster, impede amyloid formation by PrP, implicating these residues as key structural modulators in the conversion of PrP to disease-associated types of amyloid.
authors.affiliation: From the Laboratory of Persistent Viral Diseases and.
authors.forename: Allison
authors.initials: A
authors.lastname: Kraus
authors.affiliation: From the Laboratory of Persistent Viral Diseases and.
authors.forename: Kelsie J
authors.initials: KJ
authors.lastname: Anson
authors.affiliation: From the Laboratory of Persistent Viral Diseases and.
authors.forename: Lynne D
authors.initials: LD
authors.lastname: Raymond
authors.affiliation: Research Technologies Branch, Rocky Mountain Laboratories, NIAID, National Institutes of Health, Hamilton, Montana 59840.
authors.forename: Craig
authors.initials: C
authors.lastname: Martens
authors.affiliation: From the Laboratory of Persistent Viral Diseases and.
authors.forename: Bradley R
authors.initials: BR
authors.lastname: Groveman
authors.affiliation: Research Technologies Branch, Rocky Mountain Laboratories, NIAID, National Institutes of Health, Hamilton, Montana 59840.
authors.forename: David W
authors.initials: DW
authors.lastname: Dorward
authors.affiliation: From the Laboratory of Persistent Viral Diseases and bcaughey@nih.gov.
authors.forename: Byron
authors.initials: B
authors.lastname: Caughey
mesh_terms: D000682:Amyloid / Q000378:metabolism* / Q000648:ultrastructure; D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology; D017124:Conserved Sequence; D006224:Cricetinae; D019286:Endopeptidase K / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D008239:Lysine / Q000378:metabolism*; D051379:Mice; D008969:Molecular Sequence Data; D050505:Mutant Proteins / Q000737:chemistry; D009154:Mutation; D016624:Negative Staining; D018620:PrPSc Proteins / Q000378:metabolism; D011328:Prions / Q000737:chemistry* / Q000378:metabolism* / Q000648:ultrastructure; D011392:Proline / Q000378:metabolism*; D011489:Protein Denaturation; D017433:Protein Structure, Secondary; D012608:Scrapie / Q000378:metabolism; D016415:Sequence Alignment; D017550:Spectroscopy, Fourier Transform Infrared; D013329:Structure-Activity Relationship
chemical_list: D000682:Amyloid; D050505:Mutant Proteins; D018620:PrPSc Proteins; D011328:Prions; D011392:Proline; D019286:Endopeptidase K; D008239:Lysine
keywords: GSS; amyloid; lysine; prion; prion disease; proline; protein folding; protein structure