Architecture of the mycobacterial type VII secretion system

Nikolaos Famelis, Angel Rivera-Calzada, Gianluca Degliesposti, Maria Wingender, Nicole Mietrach, J. Mark Skehel, Rafael Fernandez-Leiro, Bettina Böttcher, Andreas Schlosser, Oscar Llorca () and Sebastian Geibel ()
Additional contact information
Nikolaos Famelis: Julius-Maximilians-University Würzburg
Angel Rivera-Calzada: Spanish National Cancer Research Centre (CNIO)
Gianluca Degliesposti: MRC Laboratory of Molecular Biology
Maria Wingender: Julius-Maximilians-University Würzburg
Nicole Mietrach: Julius-Maximilians-University Würzburg
J. Mark Skehel: MRC Laboratory of Molecular Biology
Rafael Fernandez-Leiro: Spanish National Cancer Research Centre (CNIO)
Bettina Böttcher: Julius-Maximilians-University Würzburg
Andreas Schlosser: Julius-Maximilians-University Würzburg
Oscar Llorca: Spanish National Cancer Research Centre (CNIO)
Sebastian Geibel: Julius-Maximilians-University Würzburg

Nature, 2019, vol. 576, issue 7786, 321-325

Abstract: Abstract Host infection by pathogenic mycobacteria, such as Mycobacterium tuberculosis, is facilitated by virulence factors that are secreted by type VII secretion systems1. A molecular understanding of the type VII secretion mechanism has been hampered owing to a lack of three-dimensional structures of the fully assembled secretion apparatus. Here we report the cryo-electron microscopy structure of a membrane-embedded core complex of the ESX-3/type VII secretion system from Mycobacterium smegmatis. The core of the ESX-3 secretion machine consists of four protein components—EccB3, EccC3, EccD3 and EccE3, in a 1:1:2:1 stoichiometry—which form two identical protomers. The EccC3 coupling protein comprises a flexible array of four ATPase domains, which are linked to the membrane through a stalk domain. The domain of unknown function (DUF) adjacent to the stalk is identified as an ATPase domain that is essential for secretion. EccB3 is predominantly periplasmatic, but a small segment crosses the membrane and contacts the stalk domain. This suggests that conformational changes in the stalk domain—triggered by substrate binding at the distal end of EccC3 and subsequent ATP hydrolysis in the DUF—could be coupled to substrate secretion to the periplasm. Our results reveal that the architecture of type VII secretion systems differs markedly from that of other known secretion machines2, and provide a structural understanding of these systems that will be useful for the design of antimicrobial strategies that target bacterial virulence.

Date: 2019
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DOI: 10.1038/s41586-019-1633-1

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