MassIVE MSV000079921

Imported Reanalysis Dataset Public PXD002772

Structural determinants of heparinâ??transforming growth factor-β1 interactions and their effects on signalling

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Description

Transforming growth factor-Ã?1 (TGF-Ã?1, Uniprot: P01137) is a heparin-binding protein that has been implicated in a number of physiological processes, including the initiation of chondrogenesis by human mesenchymal stem cells (hMSCs). Here, we identify the molecular features in the protein and in heparin required for binding and their effects on the potentiation of TGF-Ã?1â??s activity on hMSCs. Using a proteomics â??Protect and Labelâ?? approach, lysines K291, K304, K309, K315, K338, K373, K375 and K388 were identified as being directly involved in binding heparin. Competition assays in an optical biosensor demonstrated that TGF-Ã?1 does require N- and 6-O-sulfate groups for binding but that 2-O-sulfate groups are unlikely to underpin the interaction. Heparin-derived oligosaccharides as short as degree of polymerization (dp) 4 have a weak ability to compete for TGF-Ã?1 binding to heparin, which increases with the length of the oligosaccharide to reach a maximum between dp18 and dp24. In cell-based assays, heparin, 2-O-, 6-O- and N-desulfated re-N-acetylated heparin and oligosaccharides 14â??24 saccharides (dp14â??24) in length all increased the phosphorylation of SMAD2 after 6 h of stimulation with TGF-Ã?1. The results provide the structural basis for a model of heparin/heparan sulfate binding to TGF-Ã?1 and demonstrate that the features in the polysaccharide required for binding are not identical to those required for sustaining the signaling by TGF-Ã?1 in hMSCs. [dataset license: CC0 1.0 Universal (CC0 1.0)]

Keywords: heparan sulfate ; heparin ; proteoglycans ; transforming growth factor-β1

Contact

Principal Investigators:
(in alphabetical order) 		Dr Victor Nurcombe; Simon COOL
Submitting User: ccms

Publications

Lee J, Wee S, Gunaratne J, Chua RJ, Smith RA, Ling L, Fernig DG, Swaminathan K, Nurcombe V, Cool SM.
Structural determinants of heparin-transforming growth factor-β1 interactions and their effects on signaling.
Glycobiology. 2015 Dec;25(12):1491-504. Epub 2015 Aug 24.

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