title: Structural polymorphism in amyloids: new insights from studies with Y145Stop prion protein fibrils.
abstract: The C-terminally-truncated human prion protein variant Y145Stop (or PrP23-144), associated with a familial prion disease, provides a valuable model for studying the fundamental properties of protein amyloids. In previous solid-state NMR experiments, we established that the β-sheet core of the PrP23-144 amyloid is composed of two β-strand regions encompassing residues ∼113-125 and ∼130-140. The former segment contains a highly conserved hydrophobic palindrome sequence, (113)AGAAAAGA(120), which has been considered essential to PrP conformational conversion. Here, we examine the role of this segment in fibrillization of PrP23-144 using a deletion variant, Δ113-120 PrP23-144, in which the palindrome sequence is missing. Surprisingly, we find that deletion of the palindrome sequence affects neither the amyloidogenicity nor the polymerization kinetics of PrP23-144, although it does alter amyloid conformation and morphology. Using two-dimensional and three-dimensional solid-state NMR methods, we find that Δ113-120 PrP23-144 fibrils contain an altered β-core extended N-terminally to residue ∼106, encompassing residues not present in the core of wild-type PrP23-144 fibrils. The C-terminal β-strand of the core, however, is similar in both fibril types. Collectively, these data indicate that amyloid cores of PrP23-144 variants contain "essential" (i.e. nucleation-determining) and "nonessential" regions, with the latter being "movable" in amino acid sequence space. These findings reveal an intriguing new mechanism for structural polymorphism in amyloids and suggest a potential means for modulating the physicochemical properties of amyloid fibrils without compromising their polymerization characteristics.
authors: Department of Physiology and Biophysics, Case Western Reserve University, Cleveland, Ohio 44106.
authors: Eric M
authors: EM
authors: Jones
authors: Department of Chemistry, The Ohio State University, Columbus, Ohio 43210.
authors: Bo
authors: B
authors: Wu
authors: Department of Physiology and Biophysics, Case Western Reserve University, Cleveland, Ohio 44106.
authors: Krystyna
authors: K
authors: Surewicz
authors: Department of Chemistry, The Ohio State University, Columbus, Ohio 43210.
authors: Philippe S
authors: PS
authors: Nadaud
authors: Department of Chemistry, The Ohio State University, Columbus, Ohio 43210.
authors: Jonathan J
authors: JJ
authors: Helmus
authors: Department of Physiology and Biophysics, Case Western Reserve University, Cleveland, Ohio 44106.
authors: Shugui
authors: S
authors: Chen
authors: Department of Chemistry, The Ohio State University, Columbus, Ohio 43210. Electronic address: jaroniec@chemistry.ohio-state.edu.
authors: Christopher P
authors: CP
authors: Jaroniec
authors: Department of Physiology and Biophysics, Case Western Reserve University, Cleveland, Ohio 44106. Electronic address: witold.surewicz@case.edu.
authors: Witold K
authors: WK
authors: Surewicz
mesh_terms: D000682:Amyloid / Q000737:chemistry* / Q000235:genetics*; D004926:Escherichia coli / Q000378:metabolism; D017353:Gene Deletion; D006801:Humans; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy / Q000379:methods; D018625:Microscopy, Atomic Force / Q000379:methods; D011110:Polymorphism, Genetic; D017096:Prion Diseases / Q000378:metabolism; D011328:Prions / Q000737:chemistry*; D011489:Protein Denaturation; D017510:Protein Folding; D017433:Protein Structure, Secondary; D011506:Proteins / Q000737:chemistry; D017550:Spectroscopy, Fourier Transform Infrared / Q000379:methods
chemical_list: D000682:Amyloid; D011328:Prions; D011506:Proteins