Determination of Aberrant O-Glycosylation in the IgA1 Hinge Region by Electron Capture Dissociation Fourier Transform-Ion Cyclotron Resonance Mass Spectrometry

Renfrow, Matthew B.; Cooper, Helen J.; Tomana, Milan; Kulhavy, Rose; Hiki, Yoshiyuki; Toma, Kazunori; Emmett, Mark R.; Městecký, Jiří; Marshall, Alan G.; Novák, Jan

doi:10.1074/jbc.m411368200

Cited by 130 publications

(137 citation statements)

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“…Our combined ECD localization and accurate mass profiles of IgA1 HR O-glycan microheterogeneity provide a full scale picture of the range of IgA1 O-glycoforms isolated from a single source (polymeric IgA1 myeloma protein) (20,22). In our previous experiments, we observed certain IgA1 O-glycoforms for which we and others (38) fragments, we reasoned that it would be only a small contribution to the total population of Gal-deficient sites as supported by lectin Western blot analysis (Fig.…”

Section: Discussionsupporting

confidence: 55%

“…This included proximal assessment of sites with galactose (Gal)-deficient O-glycans after digests with IgAspecific proteases (8). Several studies have demonstrated the value of mass spectrometry (MS) in identifying Gal-deficient IgA1 in patients with IgAN (16 -21), including our work that demonstrated the first direct localization of native sites of O-glycan chains in the hinge region (HR) of IgA1 by use of electron capture dissociation (ECD) (20,22). ECD and the more recently developed electron transfer dissociation (ETD) have been used to identify sites of O-glycosylation on a variety of proteins (23)(24)(25)(26).…”

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confidence: 99%

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Clustered O-Glycans of IgA1

Takahashi

Wall

Suzuki

et al. 2010

Molecular & Cellular Proteomics

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Glycosylation is one of the most common post-translational modifications of proteins. It is estimated that over half of mammalian proteins are glycosylated. Patients with several autoimmune disorders, chronic inflammatory diseases, and some infectious diseases exhibit abnormal glycosylation of serum immunoglobulins and other glycoproteins (1-5). The biological functions of these modifications in health and disease have become a significant area of interest in biomedical research (6). A subset of these glycoproteins has clustered sites of O-glycosylation with serine-and threonine-rich stretches within the amino acid sequence. Mucins, such as membrane-associated MUC1, are perhaps the best known family of proteins that are heavily O-glycosylated. Their altered expression and aberrant glycosylation have made them potential targets as biomarkers for early detection of cancer (7). Immunoglobulin A1 (IgA1) 1 contains both O-and N-glycans (Fig. 1). Aberrant O-glycosylation of IgA1 is involved in the pathogenesis of IgA nephropathy (IgAN) and the closely related Henoch-Schö nlein purpura nephritis (1, 8). Interestingly, the aberrantly glycosylated molecules, IgA1 in IgAN and MUC1 in cancer, are recognized by the immune system as neoepitopes as evidenced by formation of specific antibodies (9 -11). Mucin-like bacterial surface proteins exhibit similar properties: the molecules have clustered bacterial O-glycans that mediate cellular adhesion, and blocking antibodies target these glycan-containing epitopes (12).An O-glycosylated protein from a single source contains a population of variably O-glycosylated isoforms that show a distinct distribution of microheterogeneity of the O-glycan chains in terms of number, sites of attachment, and composition. Characterizing these clustered sites and understanding how the distributions change under different biological conditions or disease states are an analytical challenge. Enzymatic or chemical release of O-glycans is not selective. The heterogeneity, composition, and quantitative aspects of different O-glycan chains can be assessed and quantified by gas chromatographic and/or mass spectrometric techniques.

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Section: Discussionsupporting

confidence: 55%

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confidence: 99%

Clustered O-Glycans of IgA1

Takahashi

Wall

Suzuki

et al. 2010

Molecular & Cellular Proteomics

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“…Fully automated chip-based nanoESI coupled to Q-FTICR at 9.4 T was recently employed for the first direct identification of multiple O-glycosylation sites in hinge region (HR) of immunoglobulin A1 (IgA1) isolated from myeloma as reported by Renfrow et al [60]. The method was designed to provide heterogeneity assay of the tryptic glycopeptide expressing various O-glycoforms and particularly detection and localization of the Gal-deficient IgA1 extracted, separated, and purified from myeloma IgA1 HR and the structural elucidation of the glycopeptides by means of electron capture dissociation (ECD)-, infrared multiphoton dissociation (IRMPD)-, and activated ion ECD (AI-ECD)-MS/MS.…”

Section: Characterization Of N-glycosylation Microheterogeneity and Smentioning

confidence: 99%

“…[66]. Reprinted by permission of The American Society for Biochemistry and Molecular Biology from [60]. [60].…”

Section: Complex Ganglioside Mixturesmentioning

confidence: 99%

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Chip electrospray mass spectrometry for carbohydrate analysis

Zamfir¹,

Bîndilă²,

Lion³

et al. 2005

Electrophoresis

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Currently two types of chip systems are used in conjunction with MS: out-of-plane devices, where hundreds of nozzles, nanospray emitters are integrated onto a single silicon substrate from which electrospray is established perpendicular to the substrate, and planar microchips, embedding a microchannel at the end of which electrospray is generated in-plane, on the edge of the microchip. In the last two years, carbohydrate research greatly benefited from the introduction and implementation of the chip-based MS. In two laboratories the advantages of the chip electrospray in terms of ionization efficiency, sensitivity, reproducibility, quality of data in combination with high mass accuracy, and resolution of detection were systematically explored for several carbohydrate classes: O-and N-glycopeptides, oligosaccharides, gangliosides and glycoprotein-derived O-and N-glycans, and glycopeptides. The current state-of-the-art in interfacing the chip electrospray devices to high-performance MS for carbohydrate analysis, and the particular requirements for method optimization in both positive and negative ion modes are reviewed here. The recent applications of these miniaturized devices and their general potential for glycomic-based surveys are highlighted.

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Glycomic Mass Spectrometric Analysis and Data Interpretation Tools

Karlsson

Packer

2009

Bioinformatics for Glycobiology and Glycomics

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Determination of Aberrant O-Glycosylation in the IgA1 Hinge Region by Electron Capture Dissociation Fourier Transform-Ion Cyclotron Resonance Mass Spectrometry

Cited by 130 publications

References 63 publications

Clustered O-Glycans of IgA1

Clustered O-Glycans of IgA1

Chip electrospray mass spectrometry for carbohydrate analysis

Glycomic Mass Spectrometric Analysis and Data Interpretation Tools

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