Structural and mechanistic basis of capsule O-acetylation in Neisseria meningitidis serogroup A

Timm Fiebig (), Johannes T. Cramer, Andrea Bethe, Petra Baruch, Ute Curth, Jana I. Führing, Falk F. R. Buettner, Ulrich Vogel, Mario Schubert, Roman Fedorov and Martina Mühlenhoff ()
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Timm Fiebig: Hannover Medical School
Johannes T. Cramer: Hannover Medical School
Andrea Bethe: Hannover Medical School
Petra Baruch: Hannover Medical School
Ute Curth: Hannover Medical School
Jana I. Führing: Hannover Medical School
Falk F. R. Buettner: Hannover Medical School
Ulrich Vogel: University of Würzburg
Mario Schubert: University of Salzburg
Roman Fedorov: Hannover Medical School
Martina Mühlenhoff: Hannover Medical School

Nature Communications, 2020, vol. 11, issue 1, 1-12

Abstract: Abstract O-Acetylation of the capsular polysaccharide (CPS) of Neisseria meningitidis serogroup A (NmA) is critical for the induction of functional immune responses, making this modification mandatory for CPS-based anti-NmA vaccines. Using comprehensive NMR studies, we demonstrate that O-acetylation stabilizes the labile anomeric phosphodiester-linkages of the NmA-CPS and occurs in position C3 and C4 of the N-acetylmannosamine units due to enzymatic transfer and non-enzymatic ester migration, respectively. To shed light on the enzymatic transfer mechanism, we solved the crystal structure of the capsule O-acetyltransferase CsaC in its apo and acceptor-bound form and of the CsaC-H228A mutant as trapped acetyl-enzyme adduct in complex with CoA. Together with the results of a comprehensive mutagenesis study, the reported structures explain the strict regioselectivity of CsaC and provide insight into the catalytic mechanism, which relies on an unexpected Gln-extension of a classical Ser-His-Asp triad, embedded in an α/β-hydrolase fold.

Date: 2020
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DOI: 10.1038/s41467-020-18464-y

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