Changes in protein conformation and assembly govern most processes in cell biology; correspondingly, defects in conformation and assembly are responsible for many human illnesses. Among the most remarkable of these are the Transmissible Spongiform Encephalopathies (TSEs), which cause neurodegenerative disease after a long latent period. The infectious agent in these diseases, the prion, is a cellular plasma-membrane protein, PrPC, that has acquired an altered, pathological conformation, PrPSc. Proteins with this altered conformation induce new PrPC molecules to switch their conformations in a slow, inexorably fatal chain reaction. It now appears that two cytoplasmically inherited genetic elements in yeast propagate by a similar mechanism, producing, instead of terminal illness, heritable changes in translational fidelity or nitrogen metabolism. All such protein conformational switches are likely to involve molecular chaperones. Work in yeast has the chaperone Hsp104 in determining the inheritance pattern of the prion-like element known as [PSI+1] which controls the rate at which ribosomes read through termination codons. Taking advantage of the many genetic and molecular techniques available in yeast, the specific aims of this proposal are 1) investigate the molecular mechanism by which Hsp104 governs the inheritance of [PSI+], 2) determine the autonomy of prion-forming domains, 3) define the essential structural features of these domains, 4) determine if other yeast proteins are capable of prion-like transformations, and 5) determine if chaperone proteins affect the structural conversions of mammalian PrP. These investigations should enhance the basic understanding of protein conformational changes in cell biology and the mechanisms of protein-conformation based inheritance.
| Kayatekin, Can; Amasino, Audra; Gaglia, Giorgio et al. (2018) Translocon Declogger Ste24 Protects against IAPP Oligomer-Induced Proteotoxicity. Cell 173:62-73.e9 |
| Frederick, Kendra K; Michaelis, Vladimir K; Caporini, Marc A et al. (2017) Combining DNP NMR with segmental and specific labeling to study a yeast prion protein strain that is not parallel in-register. Proc Natl Acad Sci U S A 114:3642-3647 |
| Frederick, Kendra K; Michaelis, Vladimir K; Corzilius, Björn et al. (2015) Sensitivity-enhanced NMR reveals alterations in protein structure by cellular milieus. Cell 163:620-8 |
| Reymer, Anna; Frederick, Kendra K; Rocha, Sandra et al. (2014) Orientation of aromatic residues in amyloid cores: structural insights into prion fiber diversity. Proc Natl Acad Sci U S A 111:17158-63 |
| Frederick, Kendra K; Debelouchina, Galia T; Kayatekin, Can et al. (2014) Distinct prion strains are defined by amyloid core structure and chaperone binding site dynamics. Chem Biol 21:295-305 |
| Kayatekin, Can; Matlack, Kent E S; Hesse, William R et al. (2014) Prion-like proteins sequester and suppress the toxicity of huntingtin exon 1. Proc Natl Acad Sci U S A 111:12085-90 |
| Lancaster, Alex K; Nutter-Upham, Andrew; Lindquist, Susan et al. (2014) PLAAC: a web and command-line application to identify proteins with prion-like amino acid composition. Bioinformatics 30:2501-2 |
| Halfmann, Randal; Wright, Jessica R; Alberti, Simon et al. (2012) Prion formation by a yeast GLFG nucleoporin. Prion 6:391-9 |
| Treusch, Sebastian; Lindquist, Susan (2012) An intrinsically disordered yeast prion arrests the cell cycle by sequestering a spindle pole body component. J Cell Biol 197:369-79 |
| Bryan Jr, Allen W; O'Donnell, Charles W; Menke, Matthew et al. (2012) STITCHER: Dynamic assembly of likely amyloid and prion ?-structures from secondary structure predictions. Proteins 80:410-20 |
Showing the most recent 10 out of 65 publications
