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, Kevin Pagel

Research output: Contribution to journalArticleAcademicpeer-review

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.

Original languageEnglish
Article number1481
Number of pages12
JournalNature Communications
Volume11
Issue number1
DOIs
Publication statusPublished - 20 Mar 2020

Fingerprint

Dive into the research topics of 'Shotgun ion mobility mass spectrometry sequencing of heparan sulfate saccharides'. Together they form a unique fingerprint.

Cite this