# Functional and pathological aggregation by prion-like domains

> **NIH NIH R35** · COLORADO STATE UNIVERSITY · 2020 · $375,420

## Abstract

PROJECT SUMMARY
Hundreds of human proteins contain prion-like domains (PrLDs), defined as domains with compositional
similarity to the yeast prion domains. In recent years, a growing number of PrLDs in various organisms have
been shown to form functional assemblies that regulate cellular activities. 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 stabilize these interactions, resulting in
dysregulation of the underlying cellular processes. Despite the importance of PrLDs in both normal physiology
and pathology, numerous basic questions remain about the regulation of functional PrLD aggregation, and the
relationship between functional and pathogenic aggregation. My lab has been a leader in efforts to define the
sequence basis for aggregation of PrLDs. During the next 5 years, we will build on this work, focusing on three
major areas: 1) We will define the sequence determinants of PrLDs that mediate the formation of dynamic
functional assemblies. In recent years, my lab and others have made substantial progress in defining how the
amino acid sequence of PrLDs affects formation of stable amyloid aggregates, but much less is known about
the sequence determinants of the dynamic multi-component assemblies formed by some PrLDs. 2) We will
examine the relationship between the dynamic functional assemblies formed by many PrLDs and the more
stable aggregates seen in various diseases. 3) We will identify additional PrLDs involved in functional protein
assemblies, and explore their mechanism of action. While PrLDs are highly over-represented in eukaryotic
genomes, 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 the
mechanism of action of these two proteins, and screen for other functional PrLDs. Collectively, these studies
will provide insight into the role of PrLDs in biological regulation and disease.

## Key facts

- **NIH application ID:** 9851874
- **Project number:** 5R35GM130352-02
- **Recipient organization:** COLORADO STATE UNIVERSITY
- **Principal Investigator:** Eric D Ross
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $375,420
- **Award type:** 5
- **Project period:** 2019-02-01 → 2024-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9851874

## Citation

> US National Institutes of Health, RePORTER application 9851874, Functional and pathological aggregation by prion-like domains (5R35GM130352-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9851874. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*