9.B.307. The FtsH AAA(+) Zinc metaloprotease (FtsH) Family
Cellular proteomes are dynamic and adjusted to permanently changing conditions by ATP-fueled proteolytic machineries. Among the five AAA+ proteases in Escherichia coli FtsH is the only essential and membrane-anchored metalloprotease. FtsH is a homohexamer that uses its ATPase domain to unfold and translocate substrates that are subsequently degraded without the need of ATP in the proteolytic chamber of the protease domain (Bittner et al. 2017). FtsH eliminates misfolded proteins in the context of general quality control and properly folded proteins for regulatory reasons. Trapping approaches have revealed a number of novel FtsH substrates. The review by Bittner et al. 2017 summarizes the substrate diversity of FtsH and presents details on the diverse recognition principles of three well-characterized substrates: LpxC, the key enzyme of lipopolysaccharide biosynthesis; RpoH, the alternative heat-shock sigma factor and YfgM, a bifunctional membrane protein implicated in periplasmic chaperone functions and cytoplasmic stress adaptation.
Crystal structures of a transmembrane helix-lacking FtsH construct from Aquifex aeolicus havebeen determined at 2.9 A (Uthoff and Baumann 2018). The FtsH hexamer is created from two different subunits of the asymmetric unit by the three-fold symmetry of the crystals. Similar to other published structures, all subunits are loaded with ADP, and the two subunits in the asymmetric unit resemble the already known open and closed conformations. Within the ATPase cycle, while the whole subunit switches from the opened to the closed state, pore loop-1 interacts with the substrate and translocates it into the proteolytic chamber. An inactive conformation of the pore loop allows the closed conformation to switch back to the opened state without pushing the substrate out again. This reveals how this new pore loop conformation is induced and how it is linked to the intersubunit signalling network (Uthoff and Baumann 2018).