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

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.