Discovery of a regulatory node that coordinates cell envelope assembly in mycobacteria
Sun, R. H.; Chen, Y.; Chng, S.-S.
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Mycobacteria possess a complex double-membrane cell envelope critical for survival and pathogenesis. Proper assembly of this architecture requires the biosynthesis and transport of major components, including arabinogalactan (AG) polysaccharides and mycolic acids (MAs), but how these processes are effectively coordinated is unknown. Here, we discover an essential membrane complex that serves as a regulatory node in mycobacterial envelope biogenesis. The acyltransferase TmaT and the arabinofuranosyltransferase AftD physically interact; cryo-EM structures reveal a 1:1 stoichiometry, and present a novel fold for TmaT, featuring a central channel that binds co-factor for acetylation in the periplasm. We establish that the TmaT-AftD interaction, and the catalytic activities of both enzymes, are required for MA transport across the cell envelope, as well as AG ligation to the cell wall, the final stage of AG biosynthesis. The TmaT-AftD complex coordinates the two major envelope assembly pathways, presenting a structural vulnerability for future anti-mycobacterial drug development.
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