Michal Chai-Danino

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.

Membrane proteins (MPs) navigate challenging biogenesis. Errors in this process are rigorously surveilled by cellular quality control to eliminate faulty MPs. The first critical challenge of this surveillance is the accurate recognition of misfolded proteins. However, how this recognition is achieved for MPs remains poorly defined. Here we reveal the specificity mechanism of FtsH, the major quality control protease clearing faulty MPs in Escherichia coli . Analyzing the in vivo degradation of two substrates, we show that lipid-facing polar residues direct substrates to FtsH-mediated degradation. Such polar residues are typically buried in the structural cores of folded MPs, and their exposure to the membrane may thus signify misfolding and flag proteins for degradation. Remarkably, lipid-facing polar residues are sufficient for recognition and can target even folded MPs for degradation. The recognition depends on the FtsH transmembrane domain. Thus, MP misfolding is sensed within the membrane to maintain a healthy membrane proteome.