Article Dans Une Revue Communications Biology Année : 2025

Structural Insights into the Protein Mannosyltransferase from Mycobacterium tuberculosis reveal a WW-Domain-Like Protein Motif in Bacteria

Résumé

We have previously demonstrated that protein-O-mannosylation (POM), a widespread post-translational glycosyl modification of proteins, is a key virulence factor of Mycobacterium tuberculosis (Mtb), the world’s deadliest infectious agent. Here, we report a detailed analysis of the structure-function relationship of MtPMT, the enzyme that catalyzes POM in Mtb. Using mutagenesis and in cellulo monitoring of POM activity, we demonstrate that, despite notable structural differences, MtPMT shares functional homologies with yeasts’ PMTs in the mechanism of the sugar transfer from lipidic donors. Furthermore, we provide evidence that the selectivity for proline-rich target glycosylation sites that differentiates MtPMT from its eukaryotic homologues, relies on a WW-like domain, which preferentially interacts with proline-rich acceptor substrate analogues. This first identification of a functional WW-like domain in a prokaryotic protein raises questions about its potential evolutionary linkage with eukaryotic WW modules and provides new insights into PMT’s acceptor-substrate recognition mechanism paving the way for the development selective inhibitors of MtPMT with potential therapeutic application against tuberculosis.

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hal-05345109 , version 1 (25-11-2025)

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Nicolas Géraud, Chloé Rivière, Camille Falcou, Gianluca Cioci, Carine Froment, et al.. Structural Insights into the Protein Mannosyltransferase from Mycobacterium tuberculosis reveal a WW-Domain-Like Protein Motif in Bacteria. Communications Biology, 2025, 8 (1), pp.1175. ⟨10.1038/s42003-025-08593-9⟩. ⟨hal-05345109⟩
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