# Membrane-embedded polar residues target membrane proteins for degradation by the quality control protease FtsH

## TL;DR

The study shows how polar residues on membrane proteins signal misfolding and trigger their degradation by the FtsH protease in E. coli.

## Contribution

The novel finding is that lipid-facing polar residues act as a degradation cue for FtsH, even in folded proteins.

## Key findings

- Lipid-facing polar residues trigger FtsH-mediated degradation of membrane proteins.
- Exposure of polar residues to the membrane can signal misfolding and promote degradation.
- Recognition by FtsH depends on its transmembrane domain and specific polar residues within it.

## 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.

Misfolded membrane proteins are toxic and must be eliminated from the cell, but how they are recognized remains unclear. Here, the authors show that polar residues facing the hydrophobic membrane act as a degradation cue sensed by E. coli FtsH protease via its transmembrane domain.