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Molecular basis for bacterial N-glycosylation by a soluble HMW1C-like N-glycosyltransferase

Author

Listed:
  • Beatriz Piniello

    (Universitat de Barcelona)

  • Javier Macías-León

    (University of Zaragoza, Mariano Esquillor s/n, Campus Rio Ebro, Edificio I+D)

  • Shun Miyazaki

    (Nagoya Institute of Technology, Gokiso-cho, Showa-ku)

  • Ana García-García

    (University of Zaragoza, Mariano Esquillor s/n, Campus Rio Ebro, Edificio I+D)

  • Ismael Compañón

    (Universidad de La Rioja, Centro de Investigación en Síntesis Química)

  • Mattia Ghirardello

    (Universidad de La Rioja, Centro de Investigación en Síntesis Química)

  • Víctor Taleb

    (University of Zaragoza, Mariano Esquillor s/n, Campus Rio Ebro, Edificio I+D)

  • Billy Veloz

    (University of Zaragoza, Mariano Esquillor s/n, Campus Rio Ebro, Edificio I+D)

  • Francisco Corzana

    (Universidad de La Rioja, Centro de Investigación en Síntesis Química)

  • Atsushi Miyagawa

    (Nagoya Institute of Technology, Gokiso-cho, Showa-ku)

  • Carme Rovira

    (Universitat de Barcelona
    Institució Catalana de Recerca i Estudis Avançats (ICREA))

  • Ramon Hurtado-Guerrero

    (University of Zaragoza, Mariano Esquillor s/n, Campus Rio Ebro, Edificio I+D
    University of Copenhagen
    Fundación ARAID)

Abstract

Soluble HMW1C-like N-glycosyltransferases (NGTs) catalyze the glycosylation of Asn residues in proteins, a process fundamental for bacterial autoaggregation, adhesion and pathogenicity. However, our understanding of their molecular mechanisms is hindered by the lack of structures of enzymatic complexes. Here, we report structures of binary and ternary NGT complexes of Aggregatibacter aphrophilus NGT (AaNGT), revealing an essential dyad of basic/acidic residues located in the N-terminal all α-domain (AAD) that intimately recognizes the Thr residue within the conserved motif Asn0-X+1-Ser/Thr+2. Poor substrates and inhibitors such as UDP-galactose and UDP-glucose mimetics adopt non-productive conformations, decreasing or impeding catalysis. QM/MM simulations rationalize these results, showing that AaNGT follows a SN2 reaction mechanism in which the acceptor asparagine uses its imidic form for catalysis and the UDP-glucose phosphate group acts as a general base. These findings provide key insights into the mechanism of NGTs and will facilitate the design of structure-based inhibitors to treat diseases caused by non-typeable H. influenzae or other Gram-negative bacteria.

Suggested Citation

  • Beatriz Piniello & Javier Macías-León & Shun Miyazaki & Ana García-García & Ismael Compañón & Mattia Ghirardello & Víctor Taleb & Billy Veloz & Francisco Corzana & Atsushi Miyagawa & Carme Rovira & Ra, 2023. "Molecular basis for bacterial N-glycosylation by a soluble HMW1C-like N-glycosyltransferase," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-41238-1
    DOI: 10.1038/s41467-023-41238-1
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    References listed on IDEAS

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    1. Matthew K. Bilyard & Henry J. Bailey & Lluís Raich & Maria A. Gafitescu & Takuya Machida & Javier Iglésias-Fernández & Seung Seo Lee & Christopher D. Spicer & Carme Rovira & Wyatt W. Yue & Benjamin G., 2018. "Palladium-mediated enzyme activation suggests multiphase initiation of glycogenesis," Nature, Nature, vol. 563(7730), pages 235-240, November.
    2. Christian Lizak & Sabina Gerber & Shin Numao & Markus Aebi & Kaspar P. Locher, 2011. "X-ray structure of a bacterial oligosaccharyltransferase," Nature, Nature, vol. 474(7351), pages 350-355, June.
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