Structural insights into terminal arabinosylation of mycobacterial cell wall arabinan

Journal article

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.

Authors: Liu, Y; Brown, CM; Erramilli, S; Su, Y-C; Guu, S-Y

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Nature Research
• Journal: Nature Communications
• Volume: 16
• Issue: 1
• Pages: 3973-3973
• Publication date: 2025-04-29
• DOI: 10.1038/s41467-025-58196-5
• EISSN: 2041-1723
• ISSN: 2041-1723
• Language: English
• Keywords: Cell envelope; Arabinogalactan; Biochemistry; Cell wall; Transmembrane domain; Tuberculosis; Periplasmic space; Chemistry; Membrane; Structural biology; Lipoarabinomannan; Mycobacterium tuberculosis; Transmembrane protein; Biology