Journal of The American Society for Mass Spectrometry

, Volume 28, Issue 9, pp 1751–1764 | Cite as

Electron-Transfer/Higher-Energy Collision Dissociation (EThcD)-Enabled Intact Glycopeptide/Glycoproteome Characterization

  • Qing Yu
  • Bowen Wang
  • Zhengwei Chen
  • Go Urabe
  • Matthew S. Glover
  • Xudong Shi
  • Lian-Wang Guo
  • K. Craig Kent
  • Lingjun Li
Focus: Using Electrons and Radical Chemistry to Characterize Biological Molecules: Research Article
First Online:
Received:
Revised:
Accepted:

Abstract

Protein glycosylation, one of the most heterogeneous post-translational modifications, can play a major role in cellular signal transduction and disease progression. Traditional mass spectrometry (MS)-based large-scale glycoprotein sequencing studies heavily rely on identifying enzymatically released glycans and their original peptide backbone separately, as there is no efficient fragmentation method to produce unbiased glycan and peptide product ions simultaneously in a single spectrum, and that can be conveniently applied to high throughput glycoproteome characterization, especially for N-glycopeptides, which can have much more branched glycan side chains than relatively less complex O-linked glycans. In this study, a redefined electron-transfer/higher-energy collision dissociation (EThcD) fragmentation scheme is applied to incorporate both glycan and peptide fragments in one single spectrum, enabling complete information to be gathered and great microheterogeneity details to be revealed. Fetuin was first utilized to prove the applicability with 19 glycopeptides and corresponding five glycosylation sites identified. Subsequent experiments tested its utility for human plasma N-glycoproteins. Large-scale studies explored N-glycoproteomics in rat carotid arteries over the course of restenosis progression to investigate the potential role of glycosylation. The integrated fragmentation scheme provides a powerful tool for the analysis of intact N-glycopeptides and N-glycoproteomics. We also anticipate this approach can be readily applied to large-scale O-glycoproteome characterization.

Graphical Abstract

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Keywords

Glycopeptide Electron-transfer dissociation EThCD High-energy collision dissociation Glycoproteomics Glycosylation 
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Notes

Acknowledgements

This research was supported in part by the National Institutes of Health grants R21AG055377, R01 DK071801 (to L.L.), R01 HL133665 (to L.W.G.), and NIH R01 HL068673 (to K.C.K.). The Orbitrap instruments were purchased through the support of an NIH shared instrument grant (NIH-NCRR S10RR029531) and Office of the Vice Chancellor for Research and Graduate Education at the University of Wisconsin-Madison. L.L. acknowledges a Vilas Distinguished Achievement Professorship and a Janis Apinis Professorship with funding provided by the Wisconsin Alumni Research Foundation and University of Wisconsin-Madison School of Pharmacy. M.S.G. acknowledges a postdoctoral fellowship supported by the National Institutes of Health, under Ruth L. Kirschstein National Research Service Award T32 HL 007936 from the National Heart Lung and Blood Institute to the University of Wisconsin-Madison Cardiovascular Research Center. The authors acknowledge Dr. Andrew Alpert from PolyLC Inc. for generous gift of the PolyHYDROXYETHYL A material. We also wish to thank Dr. Marshall Bern from Protein Metrics for providing access to Byonic software package.

Supplementary material

13361_2017_1701_MOESM1_ESM.xlsx (1.7 mb)
ESM 1 (XLSX 1695 kb)
13361_2017_1701_MOESM2_ESM.pdf (221 kb)
ESM 2 (PDF 220 kb)

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Copyright information

© American Society for Mass Spectrometry 2017

Authors and Affiliations

  • Qing Yu
    • 1
  • Bowen Wang
    • 2
  • Zhengwei Chen
    • 3
  • Go Urabe
    • 2
  • Matthew S. Glover
    • 1
    • 4
  • Xudong Shi
    • 2
  • Lian-Wang Guo
    • 2
  • K. Craig Kent
    • 5
  • Lingjun Li
    • 1
    • 3
    • 4
  1. 1.School of PharmacyUniversity of WisconsinMadisonUSA
  2. 2.Department of SurgeryWisconsin Institutes for Medical ResearchMadisonUSA
  3. 3.Department of ChemistryUniversity of WisconsinMadisonUSA
  4. 4.Cardiovascular Research Center Training Program in Translational Cardiovascular ScienceUniversity of Wisconsin-MadisonMadisonUSA
  5. 5.The Ohio State University Wexner Medical CenterColumbusUSA

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