Sialic acid mediated mechanical activation of ?₂ adrenergic receptors by bacterial pili.

ABSTRACT: Meningococcus utilizes ?-arrestin selective activation of endothelial cell ?₂ adrenergic receptor (?₂AR) to cause meningitis in humans. Molecular mechanisms of receptor activation by the pathogen and of its species selectivity remained elusive. We report that ?₂AR activation requires two asparagine-branched glycan chains with terminally exposed N-acetyl-neuraminic acid (sialic acid, Neu5Ac) residues located at a specific distance in its N-terminus, while being independent of surrounding amino-acid residues. Meningococcus triggers receptor signaling by exerting direct and hemodynamic-promoted traction forces on ?₂AR glycans. Similar activation is recapitulated with beads coated with Neu5Ac-binding lectins, submitted to mechanical stimulation. This previously unknown glycan-dependent mode of allosteric mechanical activation of a G protein-coupled receptor contributes to meningococcal species selectivity, since Neu5Ac is only abundant in humans due to the loss of CMAH, the enzyme converting Neu5Ac into N-glycolyl-neuraminic acid in other mammals. It represents an additional mechanism of evolutionary adaptation of a pathogen to its host.

SUBMITTER: Virion Z 

PROVIDER: S-EPMC6800425 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature