The binding properties of minimal oligosaccharides reveal a common heparan sulfate/dermatan sulfate-binding site in hepatocyte growth factor/scatter factor that can accommodate a wide variety of sulfation patterns.
AffiliationCancer Research UK Glyco-Oncology Group, School of Cancer and Imaging Sciences, Paterson Institute for Cancer Research, University of Manchester, Wilmslow Rd., Manchester M20 4BX, United Kingdom.
MetadataShow full item record
AbstractHeparan sulfate (HS)/heparin and dermatan sulfate (DS) both bind with high affinity to hepatocyte growth factor/scatter factor (HGF/SF) and function as necessary co-factors in vitro. How both these two structurally distinct glycosaminoglycans (GAGs) are recognized has remained unclear. We have now reconciled this issue using a panel of minimal tri- and tetrasaccharide sequences of variable but well defined sulfation patterns in combination with further development of the gel mobility shift assay to allow simultaneous comparisons of relative protein affinities/selectivities for different oligosaccharides. From this approach it would seem that a minimum binding sequence is a disulfated trisaccharide comprised of an internal iduronate flanked by monosulfated hexosamine residues and that additional sulfation further enhances affinity. However, the similarity in recognition of HS/heparin and DS seems to arise primarily from a lack of any apparent positional requirement for sulfation. Thus, isomers of HS/heparin tetrasaccharides containing only two sulfates irrespective of whether they are purely N-, 2-O-, or 6-O-sulfates bind with equivalent apparent affinity as a disulfated DS tetrasaccharide. In addition, the NMR chemical shifts induced in NK1 (the truncated variant of HGF/SF comprised of the N-terminal and first Kringle domains) by titration with either heparin or DS oligosaccharides strongly indicate that both bind to essentially the same site. Together, these observations reveal an unexpected degree of flexibility in the GAG-HGF/SF interface, allowing a single binding site in the protein to accommodate iduronate-containing sequences of variable sulfation pattern and/or density from different GAGs.
CitationThe binding properties of minimal oligosaccharides reveal a common heparan sulfate/dermatan sulfate-binding site in hepatocyte growth factor/scatter factor that can accommodate a wide variety of sulfation patterns. 2009, 284 (10):6311-21 J. Biol. Chem.
JournalThe Journal of Biological Chemistry
- The mode of action of heparan and dermatan sulfates in the regulation of hepatocyte growth factor/scatter factor.
- Authors: Lyon M, Deakin JA, Gallagher JT
- Issue date: 2002 Jan 11
- Interaction of hepatocyte growth factor with heparan sulfate. Elucidation of the major heparan sulfate structural determinants.
- Authors: Lyon M, Deakin JA, Mizuno K, Nakamura T, Gallagher JT
- Issue date: 1994 Apr 15
- The interactions of hepatocyte growth factor/scatter factor and its NK1 and NK2 variants with glycosaminoglycans using a modified gel mobility shift assay. Elucidation of the minimal size of binding and activatory oligosaccharides.
- Authors: Lyon M, Deakin JA, Lietha D, Gherardi E, Gallagher JT
- Issue date: 2004 Oct 15
- Hepatocyte growth factor/scatter factor binds to small heparin-derived oligosaccharides and stimulates the proliferation of human HaCaT keratinocytes.
- Authors: Delehedde M, Lyon M, Vidyasagar R, McDonnell TJ, Fernig DG
- Issue date: 2002 Apr 5
- Interactions of hepatocyte growth factor/scatter factor with various glycosaminoglycans reveal an important interplay between the presence of iduronate and sulfate density.
- Authors: Catlow KR, Deakin JA, Wei Z, Delehedde M, Fernig DG, Gherardi E, Gallagher JT, Pavão MS, Lyon M
- Issue date: 2008 Feb 29