Abstract

Progress in FY2012 was in the following areas: 1. 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. 2. LOW COMPLEXITY SEQUENCES. We have initiated a collaboration with the Prof. Steven McKnight of UT Southwestern to apply solid state NMR and electron microscopy to studies of homo- and hetero-association of proteins that contain """"""""low complexity sequence"""""""" (LCS) domains. A wide variety of LCS-containing proteins, some involved in mRNA export and localization of gene expression, have been identified in Prof. McKnight's lab and implicated in formation of intracellular granules that appear to be comprised of amyloid-like fibrils. Electron microscopy and preliminary solid state NMR measurements indicate that detailed molecular structural characterization will be feasible in FY13.

  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 #
1ZIADK075031-04
Application #
8553629
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
4
Fiscal Year
2012
Total Cost
$328,153
Indirect Cost

  Institution

Name
National Institute of Diabetes and Digestive and Kidney Diseases
Department
Type
DUNS #
City
State
Country
Zip Code

  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
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
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
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