Structural insights into terminal arabinosylation of mycobacterial cell wall arabinan

Yaqi Liu, Chelsea M. Brown, Satchal Erramilli, Yi-Chia Su, Shih-Yun Guu, Po-Sen Tseng, Yu-Jen Wang, Nam Ha Duong, Piotr Tokarz, Brian Kloss, Cheng-Ruei Han, Hung-Yu Chen, José Rodrigues, Kay-Hooi Khoo, Margarida Archer, Anthony A. Kossiakoff, Todd L. Lowary (), Phillip J. Stansfeld (), Rie Nygaard () and Filippo Mancia ()
Additional contact information
Yaqi Liu: Columbia University Irving Medical Center
Chelsea M. Brown: University of Warwick
Satchal Erramilli: University of Chicago
Yi-Chia Su: Academia Sinica
Shih-Yun Guu: Academia Sinica
Po-Sen Tseng: University of Alberta
Yu-Jen Wang: Academia Sinica
Nam Ha Duong: Academia Sinica
Piotr Tokarz: University of Chicago
Brian Kloss: Columbia University Irving Medical Center
Cheng-Ruei Han: Academia Sinica
Hung-Yu Chen: Academia Sinica
José Rodrigues: Universidade Nova de Lisboa (ITQB-UNL)
Kay-Hooi Khoo: Academia Sinica
Margarida Archer: Universidade Nova de Lisboa (ITQB-UNL)
Anthony A. Kossiakoff: University of Chicago
Todd L. Lowary: Academia Sinica
Phillip J. Stansfeld: University of Warwick
Rie Nygaard: Columbia University Irving Medical Center
Filippo Mancia: Columbia University Irving Medical Center

Nature Communications, 2025, vol. 16, issue 1, 1-16

Abstract: Abstract The global challenge of tuberculosis, caused by Mycobacterium tuberculosis (Mtb), is compounded by the emergence of drug-resistant strains. A critical factor in Mtb’s pathogenicity is its intricate cell envelope, which acts as a formidable barrier against immune defences and pharmacological interventions. Central to this envelope are arabinogalactan (AG) and lipoarabinomannan (LAM), two complex polysaccharides containing arabinan domains essential for maintaining cell wall structure and function. The arabinofuranosyltransferase AftB plays a pivotal role in the biosynthesis of these arabinan domains by catalyzing the addition of β-(1 → 2)-linked terminal arabinofuranose residues. Here, we present the cryo-EM structures of Mycobacterium chubuense AftB in both its apo form and bound to a donor substrate analog, resolved at 2.9 Å and 3.4 Å resolution, respectively. These structures reveal that AftB has a GT-C fold, with a transmembrane (TM) domain comprised of eleven TM helices and a periplasmic cap domain. AftB has a distinctive irregular, tube-shaped cavity that connects two proposed substrate binding sites. Through an integrated approach combining structural analysis, biochemical assays, and molecular dynamics simulations, we delineate the molecular basis of AftB’s reaction mechanism and propose a model for its catalytic function.

Date: 2025
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DOI: 10.1038/s41467-025-58196-5

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