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.
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.
|Khan, Tarique; Kandola, Tejbir S; Wu, Jianzheng et al. (2018) Quantifying Nucleation In Vivo Reveals the Physical Basis of Prion-like Phase Behavior. Mol Cell 71:155-168.e7|
|Zhang, Xiao-Feng; Sun, Rong; Guo, Qin et al. (2017) A self-perpetuating repressive state of a viral replication protein blocks superinfection by the same virus. PLoS Pathog 13:e1006253|
|Halfmann, Randal (2016) A glass menagerie of low complexity sequences. Curr Opin Struct Biol 38:18-25|
|Close, Devin W; Paul, Craig Don; Langan, Patricia S et al. (2015) Thermal green protein, an extremely stable, nonaggregating fluorescent protein created by structure-guided surface engineering. Proteins 83:1225-37|
|Cai, Xin; Chen, Jueqi; Xu, Hui et al. (2014) Prion-like polymerization underlies signal transduction in antiviral immune defense and inflammasome activation. Cell 156:1207-1222|
|Wang, Gelin; Wang, Xiaoming; Yu, Hong et al. (2013) Small-molecule activation of the TRAIL receptor DR5 in human cancer cells. Nat Chem Biol 9:84-9|
|Holmes, Daniel L; Lancaster, Alex K; Lindquist, Susan et al. (2013) Heritable remodeling of yeast multicellularity by an environmentally responsive prion. Cell 153:153-65|
|Halfmann, Randal; Wright, Jessica R; Alberti, Simon et al. (2012) Prion formation by a yeast GLFG nucleoporin. Prion 6:391-9|