Structure of an endogenous mycobacterial MCE lipid transporter

James Chen, Alice Fruhauf, Catherine Fan, Jackeline Ponce, Beatrix Ueberheide, Gira Bhabha () and Damian C. Ekiert ()
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James Chen: New York University School of Medicine
Alice Fruhauf: New York University School of Medicine
Catherine Fan: New York University School of Medicine
Jackeline Ponce: New York University School of Medicine
Beatrix Ueberheide: New York University School of Medicine
Gira Bhabha: New York University School of Medicine
Damian C. Ekiert: New York University School of Medicine

Nature, 2023, vol. 620, issue 7973, 445-452

Abstract: Abstract To replicate inside macrophages and cause tuberculosis, Mycobacterium tuberculosis must scavenge a variety of nutrients from the host1,2. The mammalian cell entry (MCE) proteins are important virulence factors in M. tuberculosis1,3, where they are encoded by large gene clusters and have been implicated in the transport of fatty acids4–7 and cholesterol1,4,8 across the impermeable mycobacterial cell envelope. Very little is known about how cargos are transported across this barrier, and it remains unclear how the approximately ten proteins encoded by a mycobacterial mce gene cluster assemble to transport cargo across the cell envelope. Here we report the cryo-electron microscopy (cryo-EM) structure of the endogenous Mce1 lipid-import machine of Mycobacterium smegmatis—a non-pathogenic relative of M. tuberculosis. The structure reveals how the proteins of the Mce1 system assemble to form an elongated ABC transporter complex that is long enough to span the cell envelope. The Mce1 complex is dominated by a curved, needle-like domain that appears to be unrelated to previously described protein structures, and creates a protected hydrophobic pathway for lipid transport across the periplasm. Our structural data revealed the presence of a subunit of the Mce1 complex, which we identified using a combination of cryo-EM and AlphaFold2, and name LucB. Our data lead to a structural model for Mce1-mediated lipid import across the mycobacterial cell envelope.

Date: 2023
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DOI: 10.1038/s41586-023-06366-0

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