Abstract
Mycobacterium tuberculosis (Mtb), which is responsible for more than a million deaths annually, uses lipids as the source of carbon and energy for its survival in the latent phase of infection. Mtb cannot synthesize all of the lipid molecules required for its growth and pathogenicity. Therefore, it relies on transporters such as the mammalian cell entry (Mce) complexes to import lipids from the host across the cell wall. Despite their importance for the survival and pathogenicity of Mtb, information on the structural properties of these proteins is not yet available. Each of the four Mce complexes in Mtb (Mce1-4) comprises six substrate-binding proteins (SBPs; MceA-F), each of which contains four conserved domains (N-terminal transmembrane, MCE, helical and C-terminal unstructured tail domains). Here, the properties of the various domains of Mtb Mce1A and Mce4A, which are involved in the import of mycolic/fatty acids and cholesterol, respectively, are reported. In the crystal structure of the MCE domain of Mce4A (MtMce4A39-140) a domain-swapped conformation is observed, whereas solution studies, including small-angle X-ray scattering (SAXS), indicate that all Mce1A and Mce4A domains are predominantly monomeric. Further, structural comparisons show interesting differences from the bacterial homologs MlaD, PqiB and LetB, which form homohexamers when assembled as functional transporter complexes. These data, and the fact that there are six SBPs in each Mtb mce operon, suggest that the MceA-F SBPs from Mce1-4 may form heterohexamers. Also, interestingly, the purification and SAXS analysis showed that the helical domains interact with the detergent micelle, suggesting that when assembled the helical domains of MceA-F may form a hydrophobic pore for lipid transport, as observed in EcPqiB. Overall, these data highlight the unique structural properties of the Mtb Mce SBPs.
Highlights
Mycobacterium tuberculosis (Mtb) is a deadly intracellular pathogen that causes the disease tuberculosis (Tb), which is responsible for more than a million deaths every year
The mammalian cell entry (Mce) proteins encoded by the mce1, mce2, mce3 and mce4 operons [Fig. 1(a)] are important proteins that play a pivotal role in the import of lipid molecules and Mtb pathogenesis (Cole et al, 1998)
We have classified the Mtb Mce1A–1F and Mce4A–4F substrate-binding proteins (SBPs) into four different domains based on secondary-structure prediction
Summary
Mycobacterium tuberculosis (Mtb) is a deadly intracellular pathogen that causes the disease tuberculosis (Tb), which is responsible for more than a million deaths every year. It is one of the very few bacteria which rely on host lipids as the source of energy and carbon for intracellular survival It converts these lipid molecules into precursors for cellmembrane remodeling, cell-wall homeostasis and pathogenesis (Cantrell et al, 2013; Santangelo et al, 2016; Queiroz & Riley, 2017; Zhang et al, 2018; Fenn et al, 2020; Alonso et al, 2020). The mammalian cell entry (Mce) proteins encoded by the mce, mce, mce and mce operons [Fig. 1(a)] are important proteins that play a pivotal role in the import of lipid molecules and Mtb pathogenesis (Cole et al, 1998) These operons are comprised of 10–14 genes each. Subsequent research has shown that the primary role of these proteins concerns lipid transport, and in addition Mce proteins are involved in modulating host cell signaling, cell-wall homeostasis and cellmembrane remodeling (Alonso et al, 2020; Fenn et al, 2020; Queiroz & Riley, 2017; Santangelo et al, 2016) and are important for the survival and pathogenesis of Mtb
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