Proteins must adopt the correct folded structure for full functionality. For some proteins, post-translational modifications have a tremendous impact on both the structure and the function of the protein. Structural regulatory control of protein function has been well- established in many facets of biology and is often a key control step in signal transduction events that are essential for life, such as the response to nutrients and stresses, cell cycle progression, and proliferation. However, unexpected alterations in protein structure can be detrimental. Misfolded proteins are frequently associated with irreversible loss-of-function and disease instead of regulation. Protein misfolding and aberrant polymerization have been implicated in many neurodegenerative disorders including Parkinson's, Alzheimer's, Huntington's, and prion diseases. We are investigating how a group of proteins adopt a specific type of """"""""misfolded"""""""" state (prion conformation) as a regulatory mechanism. These proteins may have evolved with the intrinsic ability to produce major changes in conformation as a means of regulation. This mechanism (prion propagation) provides an epigenetic switch that is self-perpetuating and is transmitted from mother cells to their daughter cells when the prion protein is transmitted through the cytoplasm. Due to their unique mode of propagation and inheritance, these prions have a profound impact on the ability of the organism to alter its phenotypes and adapt to changing environments. These prion proteins may represent remnants of an ancient regulatory mechanism that is still maintained in the budding yeast Saccharomyces cerevisiae. We now have evidence to suggest that phenotypic adaptation can be regulated by a network of prion proteins in yeast. Elucidating the underlying mechanistic principles of this epigenetic mechanism of regulation is a key first step in revealing the global impact of this type of regulation on protein expression to alter phenotypes, adaptation, and survival.

Public Health Relevance

Proper regulation of gene expression is required for normal development and cellular physiology. The loss of regulation can result in either the overexpression or insufficient expression of gene products, which in turn can lead to unregulated cell growth or premature cell death. These processes are associated with invasion of pathogens such as viruses, many human diseases, including cancer and metabolic problems.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM072778-09
Application #
8645641
Study Section
Genetic Variation and Evolution Study Section (GVE)
Program Officer
Maas, Stefan
Project Start
2005-08-01
Project End
2015-04-30
Budget Start
2014-05-01
Budget End
2015-04-30
Support Year
9
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Washington University
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Keefer, Kathryn M; Stein, Kevin C; True, Heather L (2017) Heterologous prion-forming proteins interact to cross-seed aggregation in Saccharomyces cerevisiae. Sci Rep 7:5853
Arthur, Laura L; Chung, Joyce J; Jankirama, Preetam et al. (2017) Rapid generation of hypomorphic mutations. Nat Commun 8:14112
Keefer, Kathryn M; True, Heather L (2017) A toxic imbalance of Hsp70s in Saccharomyces cerevisiae is caused by competition for cofactors. Mol Microbiol 105:860-868
Keefer, Kathryn M; True, Heather L (2016) Prion-Associated Toxicity is Rescued by Elimination of Cotranslational Chaperones. PLoS Genet 12:e1006431
Dulle, Jennifer E; Stein, Kevin C; True, Heather L (2014) Regulation of the Hsp104 middle domain activity is critical for yeast prion propagation. PLoS One 9:e87521
Westergard, Laura; True, Heather L (2014) Extracellular environment modulates the formation and propagation of particular amyloid structures. Mol Microbiol 92:698-715
Stein, Kevin C; Bengoechea, Rocio; Harms, Matthew B et al. (2014) Myopathy-causing mutations in an HSP40 chaperone disrupt processing of specific client conformers. J Biol Chem 289:21120-30
Stein, Kevin C; True, Heather L (2014) Structural variants of yeast prions show conformer-specific requirements for chaperone activity. Mol Microbiol 93:1156-71
Westergard, Laura; True, Heather L (2014) Wild yeast harbour a variety of distinct amyloid structures with strong prion-inducing capabilities. Mol Microbiol 92:183-93
Stein, Kevin C; True, Heather L (2014) Prion strains and amyloid polymorphism influence phenotypic variation. PLoS Pathog 10:e1004328

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