Progress in FY2011 was in the following areas: 1. DETERMINATION OF BETA-SHEET STRUCTURES IN YEAST PRIONS. We performed new experiments on full-length Ure2p yeast prion fibrils, showing conclusively that the fibril core is formed by the N-terminal, Asn- and Gln-rich domain and that the beta-sheet structure in the core is parallel and in-register. These results, based on solid state NMR of protease-treated fibrils, disprove an interpretation of solid state NMR data from a Swiss group, in which they claimed that the C-terminal globular domain of Ure2p is involved in the fibril core. 2. INVESTIGATIONS OF FUNCTIONAL AMYLOIDS. We have completed solid state NMR studies of Pmel17 fibrils, reported to facilitate melanin polymerization within mammalian melanosomes. The NMR data show that only about 30% of the Pmel17 repeat-domain sequence participates in the Pmel17 fibril core, and that the core structure is highly polymorphic. 3. MAMMALIAN PRION PROTEIN FIBRILS. Solid state NMR measurements on fibrils formed by recombinant mammalian PrP (full-length, Syrian hamster sequence) show that these fibrils contain parallel beta-sheets, and that the fibril core is formed primarily by a 30-residue segment near the C-terminus (collaboration with I.V. Baskakov). Although these fibrils are not infectious as prions, they may resemble infectious PrP aggregates in many respects.

Project Start
Project End
Budget Start
Budget End
Support Year
3
Fiscal Year
2011
Total Cost
$238,570
Indirect Cost
City
State
Country
Zip Code
Nagy-Smith, Katelyn; Beltramo, Peter J; Moore, Eric et al. (2017) Molecular, Local, and Network-Level Basis for the Enhanced Stiffness of Hydrogel Networks Formed from Coassembled Racemic Peptides: Predictions from Pauling and Corey. ACS Cent Sci 3:586-597
Murray, Dylan T; Kato, Masato; Lin, Yi et al. (2017) Structure of FUS Protein Fibrils and Its Relevance to Self-Assembly and Phase Separation of Low-Complexity Domains. Cell 171:615-627.e16
Nagy-Smith, Katelyn; Moore, Eric; Schneider, Joel et al. (2015) Molecular structure of monomorphic peptide fibrils within a kinetically trapped hydrogel network. Proc Natl Acad Sci U S A 112:9816-21
Gorkovskiy, Anton; Thurber, Kent R; Tycko, Robert et al. (2014) Locating folds of the in-register parallel ?-sheet of the Sup35p prion domain infectious amyloid. Proc Natl Acad Sci U S A 111:E4615-22
Tycko, Robert; Wickner, Reed B (2013) Molecular structures of amyloid and prion fibrils: consensus versus controversy. Acc Chem Res 46:1487-96
Kato, Masato; Han, Tina W; Xie, Shanhai et al. (2012) Cell-free formation of RNA granules: low complexity sequence domains form dynamic fibers within hydrogels. Cell 149:753-67
McDonald, Michele; Box, Hayden; Bian, Wen et al. (2012) Fiber diffraction data indicate a hollow core for the Alzheimer's a? 3-fold symmetric fibril. J Mol Biol 423:454-61
Kryndushkin, Dmitry S; Wickner, Reed B; Tycko, Robert (2011) The core of Ure2p prion fibrils is formed by the N-terminal segment in a parallel cross-? structure: evidence from solid-state NMR. J Mol Biol 409:263-77
Bateman, David A; Tycko, Robert; Wickner, Reed B (2011) Experimentally derived structural constraints for amyloid fibrils of wild-type transthyretin. Biophys J 101:2485-92
Hu, Kan-Nian; McGlinchey, Ryan P; Wickner, Reed B et al. (2011) Segmental polymorphism in a functional amyloid. Biophys J 101:2242-50

Showing the most recent 10 out of 18 publications