# Folding and degradation of membrane proteins

> **NIH NIH R35** · MICHIGAN STATE UNIVERSITY · 2024 · $309,749

## Abstract

ABSTRACT
(Project Title: Folding and Degradation of Membrane Proteins)
The goal of my research program is to elucidate the chemical and physical principles underlying the
folding and degradation of membrane proteins. Cells should
maintain physiologically optimal levels
of functional proteins. This is achieved by the balanced actions of molecular chaperones to facilitate
folding, proteases to degrade misfolded and superfluous proteins, and stress-response signaling
pathways to regulate levels of chaperones and proteases. This protein quality control machinery
uses multiple layers of mechanisms to monitor the folding status of a proteome. Thus, the fate of a
given protein, whether it will fold or be degraded, strongly depends on the intrinsic folding properties
of the protein. While a majority of folding and degradation studies have focused on water-soluble
proteins, it is not well understood how the intrinsic folding properties of membrane proteins affect
their degradation. The knowledge gap mainly stems from inherent difficulties in studying membrane
protein folding in their native lipid bilayer environment as well as an insufficient understanding of
folding and sequence determinants for degradation. We use a combined model employing the
membrane-integrated ATP-dependent protease FtsH of E. coli as a model degradation machine,
and the intramembrane protease GlpG of E. coli as a model substrate, both of which are widely
conserved in prokaryotic and eukaryotic cells. We developed an array of methods to study
membrane protein folding in the bilayers based on the novel steric-trapping principle. We also
developed an in vitro bilayer system to study FtsH-mediated degradation of a membrane protein.
Using these methodological innovations, my vision for future research is to learn the generalizable
lessons of folding, protein-protein interactions and quality control of membrane proteins in the cell
membranes. We will delve into three unanswered problems: 1) What is the detailed molecular
mechanisms of FtsH-mediated membrane protein degradation? 2) Is the lipid bilayer a good solvent
for the denatured states of membrane protein or a poor solvent that promotes their nonspecific
collapse? 3) How do membrane proteins from thermophilic organisms achieve their unusual
thermostability and activity? If successful, the outcome of this study will advance our fundamental
understanding of mechanisms and energetics of membrane protein degradation, identify new
physical properties of the lipid bilayer that control folding and interactions of membrane proteins,
and discover new stabilizing motifs for membrane proteins that will provide a useful design and
engineering principle.

## Key facts

- **NIH application ID:** 10794409
- **Project number:** 5R35GM144146-03
- **Recipient organization:** MICHIGAN STATE UNIVERSITY
- **Principal Investigator:** Heedeok Hong
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $309,749
- **Award type:** 5
- **Project period:** 2022-03-01 → 2027-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10794409

## Citation

> US National Institutes of Health, RePORTER application 10794409, Folding and degradation of membrane proteins (5R35GM144146-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10794409. Licensed CC0.

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