Abstract
AAA+ proteases are degradation machines, which exploit ATP hydrolysis to unfold protein substrates and translocate them through a central pore towards a degradation chamber. FtsH, a bacterial membrane-anchored AAA+ protease, plays a vital role in membrane protein quality control. Although cytoplasmic structures are described, the full-length structure of bacterial FtsH is unknown, and the route by which substrates reach the central pore remains unclear. We use electron microscopy to determine the 3D map of the full-length Aquifex aeolicus FtsH hexamer. Moreover, detergent solubilisation induces the formation of fully active FtsH dodecamers, which consist of two FtsH hexamers in a single detergent micelle. FtsH structures reveal that the cytosolic domain can tilt with respect to the membrane. A flexible linker of ~20 residues between the second transmembrane helix and the cytosolic domain permits the observed large tilting movements, thereby facilitating the entry of substrate proteins towards the central pore for translocation.
