Molecular basis for substrate transport of Mycobacterium tuberculosis ABC importer DppABCD

• Published in: Science advances 2024-03, Vol.10 (12), p.eadk8521-eadk8521
• Main Authors: Hu, Tianyu, Yang, Xiaolin, Zhu, Yuanchen, Liu, Fengjiang, Yang, Xiuna, Xiong, Zhiqi, Liang, Jingxi, Lin, Zhenli, Ran, Yuting, Guddat, Luke W, Rao, Zihe, Zhang, Bing
• Format: Article
• Language: English
• Subjects: Adenosine Triphosphate - metabolism; ATP-Binding Cassette Transporters - chemistry; Bacterial Proteins - metabolism; Biomedicine and Life Sciences; Cryoelectron Microscopy; Humans; Mycobacterium tuberculosis - metabolism; SciAdv r-articles; Structural Biology
• ISSN: 2375-2548; 2375-2548
• DOI: 10.1126/sciadv.adk8521

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 ( ). 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 DppABCD transporter in three forms, namely, the , substrate-bound, and ATP-bound states. The 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.