Structural insights into terminal arabinosylation of mycobacterial cell wall arabinan
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...
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Nature Portfolio
2025-04-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-58196-5 |
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| author | 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 Filippo Mancia |
| author_facet | 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 Filippo Mancia |
| author_sort | Yaqi Liu |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-a11afe33b3a74eb89e054cb1adfd7240 |
| institution | DOAJ |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-a11afe33b3a74eb89e054cb1adfd72402025-08-20T02:55:27ZengNature PortfolioNature Communications2041-17232025-04-0116111610.1038/s41467-025-58196-5Structural insights into terminal arabinosylation of mycobacterial cell wall arabinanYaqi Liu0Chelsea M. Brown1Satchal Erramilli2Yi-Chia Su3Shih-Yun Guu4Po-Sen Tseng5Yu-Jen Wang6Nam Ha Duong7Piotr Tokarz8Brian Kloss9Cheng-Ruei Han10Hung-Yu Chen11José Rodrigues12Kay-Hooi Khoo13Margarida Archer14Anthony A. Kossiakoff15Todd L. Lowary16Phillip J. Stansfeld17Rie Nygaard18Filippo Mancia19Department of Physiology and Cellular Biophysics, Columbia University Irving Medical CenterSchool of Life Sciences & Department of Chemistry, University of WarwickDepartment of Biochemistry and Molecular Biophysics, University of ChicagoInstitute of Biological Chemistry, Academia SinicaInstitute of Biological Chemistry, Academia SinicaDepartment of Chemistry, University of AlbertaInstitute of Biological Chemistry, Academia SinicaInstitute of Biological Chemistry, Academia SinicaDepartment of Biochemistry and Molecular Biophysics, University of ChicagoDepartment of Physiology and Cellular Biophysics, Columbia University Irving Medical CenterInstitute of Biological Chemistry, Academia SinicaInstitute of Biological Chemistry, Academia SinicaInstituto de Tecnologia Química e Biológica António Xavier, Universidade Nova de Lisboa (ITQB-UNL)Institute of Biological Chemistry, Academia SinicaInstituto de Tecnologia Química e Biológica António Xavier, Universidade Nova de Lisboa (ITQB-UNL)Department of Biochemistry and Molecular Biophysics, University of ChicagoInstitute of Biological Chemistry, Academia SinicaSchool of Life Sciences & Department of Chemistry, University of WarwickDepartment of Physiology and Cellular Biophysics, Columbia University Irving Medical CenterDepartment of Physiology and Cellular Biophysics, Columbia University Irving Medical CenterAbstract 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.https://doi.org/10.1038/s41467-025-58196-5 |
| spellingShingle | 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 Filippo Mancia Structural insights into terminal arabinosylation of mycobacterial cell wall arabinan Nature Communications |
| title | Structural insights into terminal arabinosylation of mycobacterial cell wall arabinan |
| title_full | Structural insights into terminal arabinosylation of mycobacterial cell wall arabinan |
| title_fullStr | Structural insights into terminal arabinosylation of mycobacterial cell wall arabinan |
| title_full_unstemmed | Structural insights into terminal arabinosylation of mycobacterial cell wall arabinan |
| title_short | Structural insights into terminal arabinosylation of mycobacterial cell wall arabinan |
| title_sort | structural insights into terminal arabinosylation of mycobacterial cell wall arabinan |
| url | https://doi.org/10.1038/s41467-025-58196-5 |
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