Functional and pathological aggregation by prion-like domains

PROJECT SUMMARYHundreds of human proteins contain prion-like domains (PrLDs), defined as domains with compositionalsimilarity to the yeast prion domains. In recent years, a growing number of PrLDs in various organisms havebeen shown to form functional assemblies that regulate cellular activities. Additionally, mutations in PrLDshave been linked to various degenerative disorders, including amyotrophic lateral sclerosis and frontotemporaldementia. Disease-associated mutations tend to increase the aggregation propensity of the PrLDs. Thisobservation has led to the hypothesis that many PrLDs are designed to mediate dynamic reversibleinteractions involved in cellular regulation, and that mutations stabilize these interactions, resulting indysregulation of the underlying cellular processes. Despite the importance of PrLDs in both normal physiologyand pathology, numerous basic questions remain about the regulation of functional PrLD aggregation, and therelationship between functional and pathogenic aggregation. My lab has been a leader in efforts to define thesequence basis for aggregation of PrLDs. During the next 5 years, we will build on this work, focusing on threemajor areas: 1) We will define the sequence determinants of PrLDs that mediate the formation of dynamicfunctional assemblies. In recent years, my lab and others have made substantial progress in defining how theamino acid sequence of PrLDs affects formation of stable amyloid aggregates, but much less is known aboutthe sequence determinants of the dynamic multi-component assemblies formed by some PrLDs. 2) We willexamine the relationship between the dynamic functional assemblies formed by many PrLDs and the morestable aggregates seen in various diseases. 3) We will identify additional PrLDs involved in functional proteinassemblies, and explore their mechanism of action. While PrLDs are highly over-represented in eukaryoticgenomes, the functions of only a small subset of these PrLDs is known. We have identified two new PrLD-containing proteins involved in regulation of cellular stress responses. Therefore, we will characterize themechanism of action of these two proteins, and screen for other functional PrLDs. Collectively, these studieswill provide insight into the role of PrLDs in biological regulation and disease.