# Low-complexity domain protein molecular structure, conformational dynamics, and inter-protein interactions in human health and disease

> **NIH NIH R35** · UNIVERSITY OF CALIFORNIA AT DAVIS · 2022 · $375,322

## Abstract

Project Summary/Abstract
 The dynamic assembly of biomolecules within a living cell is vital for the spatial and temporal organization
of biological function. In forming RNA granule membraneless organelles and intermediate filaments in the cell
cytoskeleton, cells leverage the self-assembly properties of protein sequences with reduced amino acid
diversity. These low complexity protein domains have only recently come to light as essential players in these
processes. Thirty percent of the proteins coded by the human genome contain a domain of this type,
highlighting the central importance of these sequences for life. In humans, pathogenic genetic mutations and
altered expression levels, in addition to functional post-translational modifications and protein-protein
interactions, modulate the assembly processes of these proteins. Linked by the common involvement of low
complexity domain proteins, this proposal outlines two lines of research focused on a fundamental mechanistic
understanding of how the proteins that compose RNA granules and intermediate filament networks assemble
to achieve the macroscopic behavior observed in living cells. A multifaceted biophysical approach employing
cutting-edge nuclear magnetic resonance and cryo-electron microscopy will allow characterization of the
molecular structure and conformational dynamics of these proteins in biologically relevant assemblies. These
biophysical studies will be coupled with other spectroscopies, biochemical assays, and protein engineering to
form more comprehensive models of how low complexity domain proteins assemble temporally and spatially.
The results of these efforts will provide a mechanistic description of how these assembly processes and their
associated control mechanisms are modulated by point mutations and altered protein expression levels linked
to motor neuron disease, dementia, muscular dystrophy, and cancer. The in vitro work proposed here will
provide detailed and testable models regarding the function of in vivo biological assemblies involved in RNA
metabolism and the cell cytoskeleton. In the broader context of human health, the molecular characterizations
of disease-relevant low complexity domain proteins and their interacting molecular partners will provide a base
of knowledge useful for the exploration of these systems as clinical biomarkers and will also facilitate the
development of antibody and small molecule therapeutics. Beyond the specific biological systems discussed in
this proposal, the tools and methodologies employed here are expected to have applicability and impact on
investigations of the thirty percent of the proteins in the human genome that contain a low complexity domain.

## Key facts

- **NIH application ID:** 10488197
- **Project number:** 5R35GM142892-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA AT DAVIS
- **Principal Investigator:** Dylan Thomas Murray
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $375,322
- **Award type:** 5
- **Project period:** 2021-09-15 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10488197

## Citation

> US National Institutes of Health, RePORTER application 10488197, Low-complexity domain protein molecular structure, conformational dynamics, and inter-protein interactions in human health and disease (5R35GM142892-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10488197. Licensed CC0.

---

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