# Role of Molecular Chaperones in Stress Response and Disease

> **NIH NIH R35** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2021 · $646,156

## Abstract

Many organisms regularly encounter fast-acting, highly proteotoxic stress conditions, including exposure to the
physiological antimicrobial hypochlorous acid (HOCl), highly elevated temperatures or acid stress. To survive
these stress conditions, they employ a class of ATP-independent, stress specific chaperones, whose
posttranslational activation is tailored towards the stress conditions that require their chaperone functions. Our
lab investigates four of these stress-specific chaperones; Hsp33, which is activated by oxidative disulfide bond
formation to protect bacteria and eukaryotic parasites against HOCl, which is commonly produced by cells of
the innate host defense; Get3, a redox-regulated Hsp33 analogue that protects yeast and likely other
eukaryotes against oxidative protein damage; HdeA, which is rapidly activated by acid-induced dissociation
and protects enteric bacteria against acid-stress encountered in the mammalian stomach; and mitochondrial
Prdx2 from Leishmania infantum, which is a temperature-regulated chaperone that protects parasites against
the sudden temperature shift as they transit from insects to warm-blooded mammals. All four of these proteins
are chaperone-inactive and stably folded under non-stress conditions but are activated following very rapid,
stress-induced conformational rearrangements, converting them into proteins with extensive regions of intrinsic
disorder. We will now combine mutational, biochemical and high-resolution structural tools to elucidate the
precise working mechanism of these proteins, testing the hypothesis that stress-induced unfolding serves to
generate novel, highly flexible protein-protein interaction sites. These studies have the potential to open up a
completely new perspective in chaperone research, protein folding and stress response pathways. In a
separate line of research, we discovered that polyphosphate (polyP), which is a universally conserved, very
abundant and ubiquitously distributed polymer, works as a highly effective protein-stabilizing scaffold. This
demonstrates that protein chaperones are not the only cellular solution to deal with proteotoxic stress
conditions. We found that polyP increases the thermostability of proteins by stabilizing them in a
predominantly β-sheet conformation. This finding helps to explain how polyP confers resistance to stress
conditions that cause protein unfolding. At the same time, it also explains how polyP acts to accelerate
processes such as bacterial biofilm formation, which depend on the stabilization of amyloid-like proteins in a
fibril-forming cross-β-sheet conformation. We recently realized that polyP equally accelerates fibril formation of
disease-associated amyloids. This activity appears to reduce the amount of toxic oligomers and, most
importantly, protects neurons against amyloid toxicity. We will now further investigate this exciting suggestion
that polyP is a physiologically important cytoprotective modifier of amyloidogenic process...

## Key facts

- **NIH application ID:** 10159934
- **Project number:** 5R35GM122506-05
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Ursula H. Jakob
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $646,156
- **Award type:** 5
- **Project period:** 2017-05-01 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10159934

## Citation

> US National Institutes of Health, RePORTER application 10159934, Role of Molecular Chaperones in Stress Response and Disease (5R35GM122506-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10159934. Licensed CC0.

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