# Relating protein interaction networks to physiology by systematic mutant analyses

> **NIH NIH R01** · UNIV OF MASSACHUSETTS MED SCH WORCESTER · 2021 · $351,750

## Abstract

Hsp90 is an essential eukaryotic chaperone that helps to produce and maintain the active state
of a select set of substrates or clients that are disproportionately linked to signaling processes
including many that promote cancer and the emergence of drug resistance in fungi. For these
reasons, inhibitor strategies to manipulate the Hsp90 chaperone system promise many potential
therapeutic benefits. Inhibitors targeting the ATPase site of Hsp90 effectively limit the
emergence of drug resistance in fungi and show promise as anti-cancer agents.
However, ATPase inhibitors block all known functions of Hsp90, leading to undesirable side
effects. In our previous work, we generated a comprehensive library of all possible mutations at
each of the 709 positions in Hsp90 and quantified the effects of each variant on yeast growth
rate as a readout of overall network function integrated over all client proteins. We will build on
this work to investigate Hsp90-client interaction mechanism. We will determine how four specific
clients are impacted by Hsp90 mutations, which will identify sites on Hsp90 that could be
targeted to inhibit specific clients. We will perform deep mutational scanning on specific client
proteins to identify the biophysical features that determine Hsp90 dependence. In addition, we
have developed a novel approach to quantify the dominant effects of Hsp90 mutations, which
we are using as a powerful new route to understand its mechanism of action. Our studies will
provide important mechanistic insights into a protein-protein interaction network that is
biologically and medically important.

## Key facts

- **NIH application ID:** 10224929
- **Project number:** 5R01GM112844-06
- **Recipient organization:** UNIV OF MASSACHUSETTS MED SCH WORCESTER
- **Principal Investigator:** DANIEL N BOLON
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $351,750
- **Award type:** 5
- **Project period:** 2015-02-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10224929

## Citation

> US National Institutes of Health, RePORTER application 10224929, Relating protein interaction networks to physiology by systematic mutant analyses (5R01GM112844-06). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10224929. Licensed CC0.

---

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