Structural and functional insights into multiple BAM-bound conformations of BepA enabling substrate triage at the outer membrane
Miyazaki, R.; Kimoto, M.; Kohga, H.; Nishi, T.; Sawasato, K.; Takahashi, Y. S.; Asai, S.; Daimon, Y.; Suzuki, T.; Laksmi, F. A.; Nugraha, Y.; Dohmae, N.; Shigematsu, H.; Narita, S.-i.; Akiyama, Y.; Tsukazaki, T.
Show abstract
The outer membrane (OM) of Gram-negative bacteria acts as a selective permeability barrier against toxic compounds, and for this function, requires proper assembly of outer membrane proteins (OMPs) by the {beta}-barrel assembly machinery (BAM) complex. A periplasmic metalloprotease BepA promotes maturation of LptD, an essential OMP, while degrades LptD intermediates aberrantly stalled at BAM. However, how BepA switches between these functions remains unclear. Here, we report cryo-EM structures of BAM- BepA complexes that capture multiple BepA conformations. In vivo crosslinking and cysteine-accessibility analyses show that possible regulatory elements, 6- and 9-loops that cover the proteolytic active site, can assume open conformations in living cells. Functional analyses reveal that 6-loop opening supports substrate interaction, degradation, and membrane association, whereas 9-loop opening is required for proteolytic activation and stabilizes BAM association. These findings provide insights into how distinct loop rearrangements regulate BepA-mediated substrate triage at BAM.
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