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Updated: Feb 25, 2026
Reconstitution of Msp1 Extraction Activity with Fully Purified Components
Published on: August 10, 2021
Membrane-embedded polar residues target membrane proteins for degradation by the quality control protease FtsH
Michal Chai-Danino1, Noy Ravensary-Modin1, Vasiliy I Vladimirov1
1Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovot, Israel.
Abstract:
The biogenesis of membrane proteins (MPs) is inherently error-prone, and is therefore monitored by quality control mechanisms that remove faulty MPs. A key challenge for this surveillance is to recognize misfolded MPs, but how this is achieved remains poorly understood. Here we reveal how FtsH, the main MP quality control protease in Escherichia coli, specifically targets faulty MPs. By analyzing the in vivo degradation of two substrates, we show that lipid-facing polar residues trigger FtsH-mediated degradation. In folded MPs, such polar residues are usually buried in the protein core. Their exposure to the membrane can therefore signal misfolding and promote degradation. Strikingly, lipid-facing polar residues can even trigger degradation of a folded protein, and do not require the extended cytosolic regions typically needed for other FtsH substrates. Recognition depends on the FtsH transmembrane domain and on specific polar residues within it. Thus, sensing misfolding within the membrane helps maintain the integrity of the membrane proteome.
Insights
Faulty membrane proteins (MPs) are degraded by the FtsH protease in E. coli. Exposed polar residues signal misfolding, triggering degradation and maintaining membrane proteome integrity.
Area of Science:
- Molecular Biology
- Cell Biology
- Proteostasis
Background:
- Membrane protein (MP) biogenesis is error-prone, necessitating quality control.
- Mechanisms for recognizing misfolded MPs remain largely unknown.
- FtsH is the primary protease responsible for MP quality control in E. coli.
Purpose of the Study:
- To elucidate how FtsH specifically targets and degrades misfolded MPs.
- To identify the molecular signals that trigger FtsH-mediated degradation.
- To understand the role of FtsH in maintaining membrane proteome integrity.
Main Methods:
- In vivo degradation assays of specific MP substrates.
- Analysis of the role of lipid-facing polar residues in FtsH recognition.
- Investigation of the FtsH transmembrane domain's function in substrate sensing.
Main Results:
- Exposure of lipid-facing polar residues in MPs signals misfolding to FtsH.
- These residues can trigger degradation even in folded proteins.
- Degradation recognition is dependent on the FtsH transmembrane domain and specific polar residues within it.
Conclusions:
- FtsH utilizes a unique mechanism to sense misfolded MPs within the membrane.
- Exposure of buried polar residues serves as a key signal for degradation.
- This surveillance system is crucial for maintaining the integrity of the membrane proteome.
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