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Shotgun ion mobility mass spectrometry sequencing of heparan sulfate saccharides

Miller, Rebecca L.; Guimond, Scott E.; Schwörer, Ralf; Zubkova, Olga V.; Tyler, Peter C.; Xu, Yongmei; Liu, Jian; Chopra, Pradeep; Boons, Geert-Jan; Grabarics, Márkó; Manz, Christian; Hofmann, Johanna; Karlsson, Niclas G.; Turnbull, Jeremy E.; Struwe, Weston B.; Pagel, Kevin

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Authors

Rebecca L. Miller

Ralf Schwörer

Olga V. Zubkova

Peter C. Tyler

Yongmei Xu

Jian Liu

Pradeep Chopra

Geert-Jan Boons

Márkó Grabarics

Christian Manz

Johanna Hofmann

Niclas G. Karlsson

Weston B. Struwe

Kevin Pagel



Abstract

Despite evident regulatory roles of heparan sulfate (HS) saccharides in numerous biological processes, definitive information on the bioactive sequences of these polymers is lacking, with only a handful of natural structures sequenced to date. Here, we develop a "Shotgun" Ion Mobility Mass Spectrometry Sequencing (SIMMS2) method in which intact HS saccharides are dissociated in an ion mobility mass spectrometer and collision cross section values of fragments measured. Matching of data for intact and fragment ions against known values for 36 fully defined HS saccharide structures (from di- to decasaccharides) permits unambiguous sequence determination of validated standards and unknown natural saccharides, notably including variants with 3O-sulfate groups. SIMMS2 analysis of two fibroblast growth factor-inhibiting hexasaccharides identified from a HS oligosaccharide library screen demonstrates that the approach allows elucidation of structure-activity relationships. SIMMS2 thus overcomes the bottleneck for decoding the informational content of functional HS motifs which is crucial for their future biomedical exploitation.

Journal Article Type Article
Acceptance Date Feb 27, 2020
Publication Date Mar 20, 2020
Journal Nature Communications
Print ISSN 2041-1723
Peer Reviewed Peer Reviewed
Volume 11
Article Number 1481
DOI https://doi.org/10.1038/s41467-020-15284-y
Keywords Epitopes, Fibroblast Growth Factors, Glucuronic Acid, Heparin, Heparitin Sulfate, Ions, Mass Spectrometry, Oligosaccharides, Sequence Analysis, Structure-Activity Relationship, Sulfotransferases
Publisher URL http://doi.org/10.1038/s41467-020-15284-y

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