Thursday, April 25, 2024
4/25/2024
PROJECT SUMMARY Hundreds of human proteins contain prion-like domains (PrLDs), defined as protein domains that are compositionally similar to yeast prion domains. In recent years, a growing number of PrLDs in various organisms have been shown to form functional assemblies that regulate various cellular activities. These assemblies vary in both complexity and material states, from highly stable amyloid aggregates that can act as a form of cellular memory to complex, reversible biomolecular condensates such as stress granules. Additionally, mutations in PrLDs have been linked to various degenerative disorders, including amyotrophic lateral sclerosis and frontotemporal dementia. Disease-associated mutations tend to increase the aggregation propensity of the PrLDs. This observation has led to the hypothesis that many PrLDs are designed to mediate dynamic reversible interactions involved in cellular regulation, and that mutations alter the dynamics of these assemblies, promote the conversion to more stable structures, or cause aberrant aggregation of the PrLDs. However, while PrLDs are highly over-represented in eukaryotic genomes, the functions of only a small fraction of PrLDs have been characterized. Our long-term goal is to develop a comprehensive understanding of the roles of PrLDs in normal physiology and in disease. Towards this end, we are examining the basis for recruitment of PrLDs to complex assemblies such as stress granules, examining how specificity of targeting is achieved between different assemblies, and characterizing novel functions of these domains. Collectively, these studies will provide a framework for understanding the diverse functions of PrLDs.
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