The quality control protease FtsH recognizes hydrophilic residues exposed to the membrane as a marker for degradation

Unfolded proteins present a major problem to the cell and are associated with a vast number of diseases. To deal with this challenge, the cell is equipped with an array of quality control factors such as proteases and chaperones. Correct recognition of unfolded proteins is essential to avoid the harmful elimination of functional proteins. While the recognition mechanism for cytosolic proteins is well researched, the mechanism for membrane proteins is largely unclear.

FtsH is the major membrane-anchored quality control protease in Escherichia coli. This protease has a cytosolic domain and a transmembrane domain. FtsH is thought to recognize its unfolded membrane substrates by its cytosolic domain, while the membrane helices serve only as an anchor. However, we show that FtsH’s degradation is mediated by recognition of polar residues in the substrate facing the bilayer.

We manage to engineer a substrate that gets rapidly degraded by FtsH although being properly folded. The substrate has one polar residue directly facing the bilayer. Moreover, elimination of membrane polar residues from another known substrate prevents its degradation. We are currently using site-specific crosslinking to identify the recognition mechanism and other factors that may be involved in the process.

Our work will elucidate a fundamental process in biology and will advance our understanding of diseases related to the quality control system.