The aggregation of proteins is deeply associated with human diseases, including dozens of familial and age-associated disorders that together comprise a major emerging health threat to our aging populace. However, recent discoveries indicate that protein aggregation can also have a wide range of structural and regulatory functions. The breadth and pervasiveness of such non-pathological aggregation is largely unexplored. In the budding yeast, Saccharomyces cerevisiae, multiple intrinsically disordered proteins (IDPs), including transcription factors, RNA- binding proteins, and kinases, have a tendency to aggregate under physiological conditions. One such protein, the transcription factor Mot3, is one of only a handful of proteins known to form self-propagating aggregates that act as protein-based elements of inheritance, or prions. By switching to and from its aggregated state, Mot3 broadens the range of phenotypes accessible to clonal yeast populations. The goals of this work are to 1) develop a quantitative flow cytometric reporter for intracellular aggregation by IDPs, 2) investigate the consequences of aggregation on the regulatory activities of IDPs, and 3) test whether aggregation by these proteins, and by Mot3 in particular, is an adaptive biological process. This work will advance our understanding of non-pathological protein aggregation, while establishing a platform for future interrogations of both functional and disease-associated aggregation in living cells.

Public Health Relevance

The aggregation of proteins is generally detrimental to their activities, and to human health. However, protein aggregates can also have important biological functions. This work will investigate the biological consequences of aggregation for a large class of previously identified aggregation-prone proteins in budding yeast. In the process, it will develop a powerful new approach for the interrogation of both functional and disease-associated protein aggregation in living cells.

Agency
National Institute of Health (NIH)
Institute
Office of The Director, National Institutes of Health (OD)
Type
Early Independence Award (DP5)
Project #
7DP5OD009152-05
Application #
9104516
Study Section
Special Emphasis Panel ()
Program Officer
Basavappa, Ravi
Project Start
2015-09-01
Project End
2016-08-31
Budget Start
2015-09-01
Budget End
2016-08-31
Support Year
5
Fiscal Year
2015
Total Cost
$330,000
Indirect Cost
$130,000
Name
Stowers Institute for Medical Research
Department
Type
DUNS #
614653652
City
Kansas City
State
MO
Country
United States
Zip Code
64110
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