CryoEM structure of an Mce/YrbE ABC transporter complex sheds light on hydrophobic transport across the envelope

Nicolas Coudray1,2,‡, Georgia L. Isom1,‡, Mark R. MacRae1,‡, Mariyah N. Saiduddin1, Gira Bhabha1,*, Damian C. Ekiert1,3,*

1 Department of Cell Biology, Skirball Institute of Biomolecular Medicine, New York University School of Medicine, New York, NY 10016, USA; 2 Applied Bioinformatics Laboratories, New York University School of Medicine, New York, NY, USA; 3 Department of Microbiology, New York University School of Medicine, New York, NY, USA; ‡ These authors contributed equally to this work

* Correspondence: damian.ekiert@ekiertlab.org; gira.bhabha@gmail.com

The Mce protein family is widespread among double-membraned bacteria, and modulates virulence in M. tuberculosis (Mtb) as well as many Gram-negative pathogens. Originally implicated in the Mammlian Cell Entry process in Mtb, mce gene clusters have since been implicated in outer membrane integrity and the transport of lipids and cholesterol. These mce operons encode numerous subunits, yet how these components assemble into a complex to drive the transport of hydrophobic molecules across the bacterial cell envelope is poorly understood. Using CryoEM, we have recently determined the structure of an Mce transporter complex from E. coli, which is unique among ABC transporters characterized to date. Despite considerable evolutionary distance between E. coli and Mtb, our structure reveals the architecture of the YrbE/MceG ABC transporter at the heart of both transport systems, as well as how this ABC transporter interacts with a hexameric ring of Mce proteins to create a hydrophobic pathway for the transport of lipids and other hydrophobic molecules. This unpublished work has yielded insights into the function of the mycobacterial mce operons, suggesting a model for how these systems may assemble and function in Mtb, and may open up avenues to the development of new antibiotics that target the essential processes of nutrient uptake and/or mycomembrane biogenesis.