She YM, Li X, Cyr TD. Remarkable Structural Diversity of N-Glycan Sulfation on Influenza Vaccines. Anal Chem. 2019 Mar 25.
Sulfated N-glycans are biologically important structures derived from enzymatically post-glycosylational modifications of glycoproteins in many therapeutic biologics. The high-throughput analysis of sulfated N-glycomes remains a daunting technical challenge due to negatively charged heterogeneous composition, large molecular structures, lability of sulfate attachments, and a lack of highly selective enrichment methods. Using liquid chromatography-mass spectrometry, we have analyzed the N-glycans of influenza viral hemagglutinin and neuraminidase from several subtypes of influenza vaccines, and utilized the existing resource to establish an N-glycan library consisting of 927 N-glycan structures and 387 sulfated N-glycan compositions. With the aid of database for data mining, 1380 unique N-glycopeptides were identified and manually validated by de novo glycopeptide sequencing, of which 514 were sulfated at the site-specific locations. We report here a mass spectrometric method that is able to identify and distinguish the isobaric structures of complex and hybrid N-glycans flanked by a terminal sulfation sequon on Gal-GlcNAc and GalNAc-GlcNAc of sulfated-3-Gal, sulfated-6-GlcNAc and sulfated-4-GalNAc. The database-aided glycoproteomic analyses enable rapid determination of new sulfated-N-glycan structures in large sets of influenza vaccines, including those highly branched non-sialyl sulfo-N-glycans bearing lactosaminic extensions in both complex and hybrid N-glycans that especially interact with sulfotransferases. The novel findings highlight the tremendous structural diversity of sulfated N-glycans, and strongly suggest potential functional importance of N-glycan sulfation of influenza glycoproteins.
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