Shotgun ion mobility mass spectrometry sequencing of heparan sulfate saccharides

Rebecca L. Miller (), Scott E. Guimond, 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, Jeremy E. Turnbull, Weston B. Struwe and Kevin Pagel
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Rebecca L. Miller: University of Copenhagen
Scott E. Guimond: University of Liverpool
Ralf Schwörer: Ferrier Research Institute, Victoria University of Wellington, 69 Gracefield Road, Gracefield
Olga V. Zubkova: Ferrier Research Institute, Victoria University of Wellington, 69 Gracefield Road, Gracefield
Peter C. Tyler: Ferrier Research Institute, Victoria University of Wellington, 69 Gracefield Road, Gracefield
Yongmei Xu: University of North Carolina
Jian Liu: University of North Carolina
Pradeep Chopra: University of Georgia
Geert-Jan Boons: University of Georgia
Márkó Grabarics: Freie Universitaet Berlin, Institute of Chemistry and Biochemistry
Christian Manz: Freie Universitaet Berlin, Institute of Chemistry and Biochemistry
Johanna Hofmann: Freie Universitaet Berlin, Institute of Chemistry and Biochemistry
Niclas G. Karlsson: University of Gothenburg
Jeremy E. Turnbull: University of Copenhagen
Weston B. Struwe: University of Oxford
Kevin Pagel: Freie Universitaet Berlin, Institute of Chemistry and Biochemistry

Nature Communications, 2020, vol. 11, issue 1, 1-12

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-15284-y

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