4.6 Article

Structural Polymorphism in Amyloids NEW INSIGHTS FROM STUDIES WITH Y145Stop PRION PROTEIN FIBRILS

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JOURNAL OF BIOLOGICAL CHEMISTRY
卷 286, 期 49, 页码 42777-42784

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AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M111.302539

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  1. National Institutes of Health [R01NS038604, R01NS044158, R01GM094357]

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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 beta-sheet core of the PrP23-144 amyloid is composed of two beta-strand regions encompassing residues similar to 113-125 and similar to 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, Delta 113-120 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 Delta 113-120 PrP23-144 fibrils contain an altered beta-core extended N-terminally to residue similar to 106, encompassing residues not present in the core of wild-type PrP23-144 fibrils. The C-terminal beta-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.

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