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Title: A structural study of fibroblast growth factor 18
Author: Adam, L. E.
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 2006
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The Fibroblast Growth Factor (FGF) family is heavily involved in development and cancer, in roles such as cell differentiation, mitosis, survival and proliferation. Although it is slowly being appreciated that the eighteen members are tightly controlled within such a broad role, the underlying mechanisms are not fully understood. Structural studies of FGF signalling components are illuminating the means of specificity, but these are by no way extensive. Only a small proportion of the family have been structurally determined, and the nature of the interactions with the receptors (FGFRs) and heparin sulphate (HS) are still controversial. In order to investigate the means of FGF signalling specificity, I cloned and expressed FGF18. A method of procuring soluble protein was devised, and this protein was purified and prepared for crystallisation. I ascertained the structure to 3Å resolution following crystallisation and X-ray analysis, and revealed how FGF18 contains a flexible β4-β5 loop that is proposed to determine receptor isoforms affinity. An attempt to form FGF18-FGFR complexes was carried out, with both FGFR4 and FGFR2c. FGFR4 was cloned and purification protocols were tested. FGFR2c was prepared, and strong evidence of FGF18-FGFR2 complex formation was gathered using biochemical techniques. The crystallisation of FGF18 was extended to the heparin-bound form, in order to determine the high affinity binding site. The 2.6Å structure revealed a novel heparin binding trajectory across the FGF18 surface as well as enhancing the protein structural data. A comparative study with the structures of other FGFs was carried out with regards to the heparin binding surface, and this highlighted structural explanations for biological activity.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available