Fts H / Hfl B

Abstract

The ATP‐dependent, membrane‐standing metalloprotease FtsH/HflB (filamentation temperature‐sensitive locus H/high frequency of lysogenisation locus B) is universally conserved in eubacteria, chloroplasts, and mitochondria. Its substrates are integral membrane proteins, for example, it degrades the unassembled subunits such as SecY of the SecYEG translocon or the a‐subunit of F o ATPase, as well as some soluble proteins, most notably the heat shock factor σ 32 , the λ‐phage transcriptional activator λ‐CII and LpxC, a key enzyme in lipid A biosynthesis. FtsH is the only essential energy‐dependent protease in Escherichia coli and its knockout shows generally severe phenotypes, for example, malfunctioning of paraplegin, a close homolog in human mitochondria, results in one form of spastic paraplegia. The crystal structure of the cytosolic region reported here reveals a self‐compartmentalizing protease composed of two hexameric rings. The protease ring exhibits perfect sixfold symmetry with a novel, virtually all‐helical fold of the monomers. The active center is formed by the 427 HEAGH motif and the conserved Asp500 as third zing ligand. The AAA domains have ADP bound and are arranged in a hexameric ring with twofold symmetry only. Two of the essential pore residues Phe234, which are implied in substrate binding and translocation, are located toward the interior of the two rings. This suggests a mechanism of substrate recognition and unfolding.