# Single Molecule Biophysics of Intrinsically Disordered Proteins in Disease

> **NIH NIH F99** · WASHINGTON UNIVERSITY · 2021 · $31,536

## Abstract

Abstract: Intrinsically disordered proteins (IDPs) are found in over 50% of human proteins where they play essential roles
in a wide range of cellular functions including transcriptional regulation, DNA repair, cell signaling, and apoptosis. As a
result of their importance in key processes associated with cellular growth, proliferation, and death, proteins containing
IDPs are often associated with cancer. The ability of IDPs to adopt a wide range of conformations raises a number of key
challenges to standard biochemical, biophysical, and computational techniques. Despite these challenges, our ability to treat
many cancers depends on an understanding of the molecular basis for diseases. This, in turn, presents a pressing need to
understand the mechanistic basis of IDP function and dysfunction. This proposal will study protein-nucleic acid interactions
driven by intrinsically disordered proteins in two pressing diseases: COVID-19 and cancer. For the F99 phase (Aim 1) of
the award, I will build upon my computational and experimental biophysics training to continue investigating the SARS-
CoV-2 nucleocapsid protein and its ability to package its viral genome. The COVID-19 pandemic, preceded by previous
coronavirus outbreaks caused by SARS and MERS, necessitates study of these viruses in order to better combat them.
Coronaviruses contain large RNA genomes that are packaged into a relatively small virion, mediated by the nucleocapsid
protein, a highly disordered multidomain RNA binding protein. A current outstanding question is how SARS-CoV-2
package their 30 kb genomes into a relatively small (<100 nm) virion. The conserved structural motifs in coronavirus
genomes known as packaging signals has been shown to confer genome specificity, yet the relationship between packaging
signals and genome compaction are opaque. My thesis work combines single-molecule fluorescence spectroscopy with all-
atom and coarse-grained simulations to construct a mechanistic understanding of how N protein drives RNA packaging.
Success of this project will reveal the role of IDP-encoded multivalency in selective genome packaging. Since the
architecture of the nucleocapsid protein is conserved throughout coronaviruses it will also present new insight into
mechanisms that can be broadly targeted for therapeutic intervention. The K00 phase (Aim 2) of this proposal will study
the contribution of IDPs in transcriptional regulation, genome organization and cancer development. Fusion-oncogenes are
a common genetic translocation event which often involve a DNA binding domain becoming fused to an IDP. During the
post-doctoral phase I will obtain training in super-resolution microscopy to investigate the effects of transcriptionally active
fusion-oncogenes. Several studies have shown that IDPs from transcription factors drive the formation of transcriptional
assemblies (transcriptional condensates) at sites of gene expression. I will test the hypothesis that fusion-oncoproteins lead
to ...

## Key facts

- **NIH application ID:** 10305403
- **Project number:** 1F99CA264413-01
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Jhullian Jamille Alston
- **Activity code:** F99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $31,536
- **Award type:** 1
- **Project period:** 2021-09-01 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10305403

## Citation

> US National Institutes of Health, RePORTER application 10305403, Single Molecule Biophysics of Intrinsically Disordered Proteins in Disease (1F99CA264413-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10305403. Licensed CC0.

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