Dataset Information

Sialic acid-mediated mechanical activation of β2 adrenergic receptors by bacterial pili

ABSTRACT: Meningococcus utilizes β-arrestin selective activation of endothelial cell β2 adrenergic receptor (β2AR) to cause meningitis in humans. Molecular mechanisms of receptor activation by the pathogen and of its species selectivity remained elusive. We report that β2AR 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 N34 terminus, while being independent of surrounding amino-acid residues. Meningococcus triggers receptor signaling by exerting direct and hemodynamic-promoted traction forces on β2AR 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.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Blood

SUBMITTER: François GUILLONNEAU

LAB HEAD: Stephano Marullo M.D. Ph.D.

PROVIDER: PXD015389 | Pride | 2019-11-12

REPOSITORIES: Pride

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Dataset's files

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			Action	DRS
	StMO190307_10pccorr_1_WT_Q29550.dat	Other
	StMO190307_10pccorr_1_WT_Q29550.mgf	Mgf
	StMO190307_10pccorr_1_WT_Q29550.mzid	Mzid
	StMO190307_10pccorr_1_WT_Q29550.raw	Raw
	StMO190307_detailed_manualdatasearchfiguresandlegends.pdf	Pdf

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Sialic acid mediated mechanical activation of β2 adrenergic receptors by bacterial pili.

Virion Zoe Z Doly Stéphane S Saha Kusumika K Lambert Mireille M Guillonneau François F Bied Camille C Duke Rebecca M RM Rudd Pauline M PM Robbe-Masselot Catherine C Nassif Xavier X Coureuil Mathieu M Marullo Stefano S

Nature communications 20191018 1

Meningococcus utilizes β-arrestin selective activation of endothelial cell β2 adrenergic receptor (β2AR) to cause meningitis in humans. Molecular mechanisms of receptor activation by the pathogen and of its species selectivity remained elusive. We report that β2AR 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 in ...[more]

PMID: 31628314

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Project description:Glycosylation of proteins is one of the most common post-translational modification (PTM) and plays important regulatory functions in diverse biological processes such as protein stability or cell signaling. Accordingly, glycoproteins are also a consistent part of the human tear film proteome maintaining the proper function of the ocular surface and forming the first defense barrier of the ocular immune system. Irregularities in the glycoproteomic composition of the tear film might promote development of chronic eye diseases indicating glycoproteins as valuable source for biomarker discovery or drug target identification. The present study aimed to develop a lectin-based affinity method for the enrichment and concentration of tear glycoproteins/glycopeptides and the characterization of their specific N-glycosylation sites by high-resolution mass spectrometry (MS). For method development and evaluation, we accumulated first native glycoproteins from human tear sample pools and assessed the enrichment efficiency of different lectin column systems by 1D gel electrophoresis and specific protein stainings (Coomassie and glycoproteins). The best-performing multi-lectin column system (comprising the four lectins ConA, JAC, WGA and UEA I, termed as 4L) was applied for glycopeptide enrichment from human tear sample digests followed by MS-based detection and localization of their specific N-glycosylation sites. As main result, the present study identified in total 26 N glycosylation sites of 11 N-glycoproteins in tear sample pools of healthy individuals (n=3 biological sample pools). Amongst others, we identified tear film proteins lactotransferrin (N497 and N642, LTF), Ig heavy chain constant α-1 (N144 and 340, IGHA1), prolactin-inducible protein (N105, PIP) as well as extracellular lacritin (N105, LACRT) as highly reliable and significant N glycoproteins, which were already associated with the pathogenesis of various chronic eye diseases such as the dry eye syndrome (DES). In conclusion, the results of the present study will serve as important tear film N-glycoprotein catalogue for future studies focusing the human tear film and ocular surface-related inflammatory diseases.

Dataset Information

Sialic acid-mediated mechanical activation of β2 adrenergic receptors by bacterial pili

Dataset's files

Publications

Sialic acid mediated mechanical activation of β<sub>2</sub> adrenergic receptors by bacterial pili.

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