Molecular basis for substrate transport of Mycobacterium tuberculosis ABC importer DppABCD

Abstract

The type I adenosine 5′-triphosphate (ATP)–binding cassette (ABC) transporter DppABCD is believed to be responsible for the import of exogenous heme as an iron source into the cytoplasm of the human pathogen Mycobacterium tuberculosis ( Mtb ). Additionally, this system is also known to be involved in the acquisition of tri- or tetra-peptides. Here, we report the cryo–electron microscopy structures of the dual-function Mtb DppABCD transporter in three forms, namely, the apo , substrate-bound, and ATP-bound states. The apo structure reveals an unexpected and previously uncharacterized assembly mode for ABC importers, where the lipoprotein DppA, a cluster C substrate-binding protein (SBP), stands upright on the translocator DppBCD primarily through its hinge region and N-lobe. These structural data, along with biochemical studies, reveal the assembly of DppABCD complex and the detailed mechanism of DppABCD-mediated transport. Together, these findings provide a molecular roadmap for understanding the transport mechanism of a cluster C SBP and its translocator.