A conserved membrane protein negatively regulates Mce1 complexes in mycobacteria

Abstract

AbstractTuberculosis (TB) continues to pose a serious threat to global health.Mycobacterium tuberculosis, the causative agent of TB, is an intracellular pathogen that relies on various mechanisms to survive and persist within the host. Among their many virulence factors, mycobacteria encode Mce systems, putative transporters that are important for lipid uptake; the molecular basis for Mce function(s) is poorly understood. To gain insights into the composition and architecture of Mce systems, we characterized the putative Mce1 complex involved in fatty acid transport. We show that the Mce1 system inMycobacterium smegmatiscomprises a canonical ATP-binding cassette transporter, associated with functionally redundant heterohexameric assemblies of substrate-binding proteins. Furthermore, we establish that the conserved membrane protein Mce1N negatively regulates Mce1 function via a unique mechanism involving blocking transporter assembly. Our work offers molecular understanding of Mce complexes, sheds light on mycobacterial lipid metabolism and its regulation, and informs future anti-mycobacterial strategies.