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The membrane-bound AAA protease FtsH is the key player controlling protein quality in bacteria. Two single-pass membrane proteins, HflK and HflC, interact with FtsH to modulate its proteolytic activity. Here, we present structure of the entire FtsH-HflKC complex, comprising 12 copies of both HflK and HflC, all of which interact reciprocally to form a cage, as well as four FtsH hexamers with periplasmic domains and transmembrane helices enclosed inside the cage and cytoplasmic domains situated at the base of the cage. FtsH K61/D62/S63 in the β2-β3 loop in the periplasmic domain directly interact with HflK, contributing to complex formation. Pull-down and in vivo enzymatic activity assays validate the importance of the interacting interface for FtsH-HflKC complex formation. Structural comparison with the substrate-bound human m-AAA protease AFG3L2 offers implications for the HflKC cage in modulating substrate access to FtsH. Together, our findings provide a better understanding of FtsH-type AAA protease holoenzyme assembly and regulation. [Display omitted] • Cryo-EM structure of the entire FtsH-HflKC complex is solved • 12 HflK and HflC interact with each other and encompass 4 FtsH hexamers • HflK interacts with the FtsH β2-β3 loop to contribute to complex formation • The cytoplasmic domain and the transmembrane helices of FtsH are featured Qiao et al. solved the Escherichia coli AAA protease FtsH together with its modulator HflKC complex, revealing that 12 HflK interact extensively and reciprocally with 12 HflC to encompass 4 FtsH hexamers through HflK and the FtsH β2-β3 loop. [ABSTRACT FROM AUTHOR]