Structural Studies of Prion Fibrils and Other Protein Fibrils

Tycko, Robert

Abstract

Progress in FY2017 was in the following areas: LOW COMPLEXITY SEQUENCES. In collaboration with Prof. Steven McKnight (UT Southwestern Medical Center) and his colleagues, we have completed an extensive set of solid state NMR and electron microscopy measurements on fibrils formed by the low complexity domain of the fused in sarcoma protein (FUS-LC). From these data, we have determined a full molecular structure for FUS-LC fibrils, representing the first structure determination of a low complexity protein assembly. Interestingly, the fibril core is formed by a specific 57-residue segment within the 214-residue FUS-LC sequence, despite the overall self-similarity and repetitive nature of the sequence. A paper describing these results has been accepted for publication in Cell. In related work, we have used solid state NMR to show that a critical aspartate residue in the low-complexity domain of the hnRNPA2 protein (Asp290) residues in an in-register, parallel cross-beta structure in hnRNPA2 fibrils. This result explains why mutation of this aspartate residue to valine leads to frontotemporal dementia and amyotrophic lateral sclerosis, by stabilizing the cross-beta fibril structure. A paper describing these results is in preparation.

Funding Agency

• Agency: National Institute of Health (NIH)
• Institute: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
• Type: Investigator-Initiated Intramural Research Projects (ZIA)
• Project #: 1ZIADK075031-09
• Application #: 9565924
• Support Year: 9
• Fiscal Year: 2017

Institution

• Name: U.S. National Inst Diabetes/Digst/Kidney

Publications

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