Glycomics using mass spectrometry

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Abstract

Mass spectrometry plays an increasingly important role in structural glycomics. This review provides an overview on currently used mass spectrometric approaches such as the characterization of glycans, the analysis of glycopeptides obtained by proteolytic cleavage of proteins and the analysis of glycosphingolipids. The given examples are demonstrating the application of mass spectrometry to study glycosylation changes associated with congenital disorders of glycosylation, lysosomal storage diseases, autoimmune diseases and cancer.

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Intravenous gammaglobulin suppresses inflammation through a novel T(H)2 pathway.

Robert M Anthony, Toshihiko Kobayashi, Fredrik Wermeling … (2011)

High-dose intravenous immunoglobulin is a widely used therapeutic preparation of highly purified immunoglobulin G (IgG) antibodies. It is administered at high doses (1-2 grams per kilogram) for the suppression of autoantibody-triggered inflammation in a variety of clinical settings. This anti-inflammatory activity of intravenous immunoglobulin is triggered by a minor population of IgG crystallizable fragments (Fcs), with glycans terminating in α2,6 sialic acids (sFc) that target myeloid regulatory cells expressing the lectin dendritic-cell-specific ICAM-3 grabbing non-integrin (DC-SIGN; also known as CD209). Here, to characterize this response in detail, we generated humanized DC-SIGN mice (hDC-SIGN), and demonstrate that the anti-inflammatory activity of intravenous immunoglobulin can be recapitulated by the transfer of bone-marrow-derived sFc-treated hDC-SIGN(+) macrophages or dendritic cells into naive recipients. Furthermore, sFc administration results in the production of IL-33, which, in turn, induces expansion of IL-4-producing basophils that promote increased expression of the inhibitory Fc receptor FcγRIIB on effector macrophages. Systemic administration of the T(H)2 cytokines IL-33 or IL-4 upregulates FcγRIIB on macrophages, and suppresses serum-induced arthritis. Consistent with these results, transfer of IL-33-treated basophils suppressed induced arthritic inflammation. This novel DC-SIGN-T(H)2 pathway initiated by an endogenous ligand, sFc, provides an intrinsic mechanism for maintaining immune homeostasis that could be manipulated to provide therapeutic benefit in autoimmune diseases. ©2011 Macmillan Publishers Limited. All rights reserved

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A systematic approach to protein glycosylation analysis: a path through the maze.

Jayesh Kattla, P Rudd, Karina Mariño … (2010)

Protein glycosylation is an important post-translational modification. It is a feature that enhances the functional diversity of proteins and influences their biological activity. A wide range of functions for glycans have been described, from structural roles to participation in molecular trafficking, self-recognition and clearance. Understanding the basis of these functions is challenging because the biosynthetic machinery that constructs glycans executes sequential and competitive steps that result in a mixture of glycosylated variants (glycoforms) for each glycoprotein. Additionally, naturally occurring glycoproteins are often present at low levels, putting pressure on the sensitivity of the analytical technologies. No universal method for the rapid and reliable identification of glycan structure is currently available; hence, research goals must dictate the best method or combination of methods. To this end, we introduce some of the major technologies routinely used for structural N- and O-glycan analysis, describing the complementary information that each provides.

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Mapping Intact Protein Isoforms in Discovery Mode Using Top Down Proteomics

John C Tran, Leonid Zamdborg, Dorothy Ahlf … (2011)

A full description of the human proteome relies on the challenging task of detecting mature and changing forms of protein molecules in the body. Large scale proteome analysis 1 has routinely involved digesting intact proteins followed by inferred protein identification using mass spectrometry (MS) 2 . This “bottom up” process affords a high number of identifications (not always unique to a single gene). However, complications arise from incomplete or ambiguous 2 characterization of alternative splice forms, diverse modifications (e.g., acetylation and methylation), and endogenous protein cleavages, especially when combinations of these create complex patterns of intact protein isoforms and species 3 . “Top down” interrogation of whole proteins can overcome these problems for individual proteins 4,5 , but has not been achieved on a proteome scale due to the lack of intact protein fractionation methods that are well integrated with tandem MS. Here we show, using a new four dimensional (4D) separation system, identification of 1,043 gene products from human cells that are dispersed into >3,000 protein species created by post-translational modification, RNA splicing, and proteolysis. The overall system produced >20-fold increases in both separation power and proteome coverage, enabling the identification of proteins up to 105 kilodaltons and those with up to 11 transmembrane helices. Many previously undetected isoforms of endogenous human proteins were mapped, including changes in multiply-modified species in response to accelerated cellular aging (senescence) induced by DNA damage. Integrated with the latest version of the Swiss-Prot database 6 , the data provide precise correlations to individual genes and proof-of-concept for large scale interrogation of whole protein molecules. The technology promises to improve the link between proteomics data and complex phenotypes in basic biology and disease research 7 .

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Author and article information

Contributors

: M.Wuhrer@lumc.nl

Journal

Journal ID (nlm-ta): Glycoconj J

Journal ID (iso-abbrev): Glycoconj. J

Title: Glycoconjugate Journal

Publisher: Springer US (Boston )

ISSN (Print): 0282-0080

ISSN (Electronic): 1573-4986

Publication date (Electronic): 25 April 2012

Publication date PMC-release: 25 April 2012

Publication date (Print): January 2013

Volume: 30

Issue: 1

Pages: 11-22

Affiliations

Department of Parasitology, Biomolecular Mass Spectrometry Unit, Leiden University Medical Center, Albinusdreef 2, 2333ZA Leiden, The Netherlands

Article

Publisher ID: 9376

DOI: 10.1007/s10719-012-9376-3

PMC ID: 3547245

PubMed ID: 22532006

SO-VID: b4aeb63b-8d8d-4803-a4ef-000fc493c8cf

History

Date received : 7 February 2012

Date revision received : 29 March 2012

Date accepted : 2 April 2012

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ScienceOpen disciplines: Biochemistry

Keywords: cancer,congentical disorders of glycosylation,lysosomal storage diseases,maldi-tof-ms,permethylation

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ScienceOpen disciplines: Biochemistry

Keywords: cancer, congentical disorders of glycosylation, lysosomal storage diseases, maldi-tof-ms, permethylation

Glycomics using mass spectrometry

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Abstract

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Most cited references 72

Intravenous gammaglobulin suppresses inflammation through a novel T(H)2 pathway.

A systematic approach to protein glycosylation analysis: a path through the maze.

Mapping Intact Protein Isoforms in Discovery Mode Using Top Down Proteomics

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