An investigation into the location of the heparan sulphate/heparin-binding site of human bone morphogenetic protein-7

David McClarence

Research output: ThesisDoctoral Thesis

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The bone morphogenetic proteins (BMPs) are small cystine-knot-containing cytokines that serve pivotal functions during the development of a wide range of tissues. Consisting of approximately twenty structurally and functionally related proteins, the BMP family makes up the largest branch of the transforming growth factor beta (TGF-β) superfamily. At least three of the BMPs have the ability to bind to heparan sulphate (HS) and heparin, which are highly sulphated, complex polysaccharides that are found in abundance on cell surfaces and in the extracellular matrix. The functional significance of these interactions remains unclear, but it has been demonstrated that BMPs -2 and -4 bind to HS/heparin via a small cluster of basic amino acids in their N-terminal regions. BMP-7 has also been shown to interact with HS and heparin. However, it belongs to a different BMP sub-group to BMPs -2 and -4, and it differs from them considerably in this key N-terminal region. This raises the question as to where the HS/heparin-binding site of BMP-7 is situated. The aim of this study was to answer this question using a combination of predictive computational molecular docking calculations, site-directed mutagenesis techniques and heparin-affinity chromatography.

The findings from a series of predictive docking calculations suggested that BMP-7 binds to HS/heparin through three basic residues close to the C-terminal ends of each of its constituent monomers. However, experimental studies have shown that this is unlikely, as removing two of these three basic residues from each monomer had no affect on the heparin-binding affinity of BMP-7. The same was true when two of seven basic residues were removed from the N-terminal regions of each BMP-7 monomer, both alone and in combination with the C-terminal mutations. Further investigation is therefore required in order to resolve this matter.

Original languageEnglish
Awarding Institution
  • Royal Holloway, University of London
Award date1 Nov 2011
Publication statusUnpublished - 2011

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