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Structure-function studies of fibroblast growth factors (FGFS)

Citation

Zhu, Xiaotian (1993) Structure-function studies of fibroblast growth factors (FGFS). Dissertation (Ph.D.), California Institute of Technology. https://resolver.caltech.edu/CaltechTHESIS:01102013-134402009

Abstract

The fibroblast growth factor (FGF) family exhibits mitogenic, chemotactic and angiogenic activity in a variety of cell types. The first three-dimensional structures of two members of the FGF family, bovine acidic FGF (aFGF) and human basic FGF (bFGF), have been crystallographically determined by multiple isomorphous replacement (MIR), and refined to 2.7 Å and 1.9 Å respectively. The structures of both aFGF and bFGF consist of twelve antiparallel β strands which are arranged in a folding pattern with approximate three-fold internal symmetry. A striking feature of the FGF structures is the overall similarity to the structures of soybean trypsin inhibitor and interleukins-1α and 1β, in spite of the low sequence homology between these proteins.

FGF stimulates cellular proliferation and differentiation through the interactions with both the cell surface FGF receptor and heparin. In the FGF structures, the two putative receptor binding sites are located on different sides of FGF. Also, a region rich in positively charged amino acids that is likely involved in heparin binding has been found in the FGF structures. It is further shown that the putative heparin and receptor binding regions occupy distinct locations on the protein surface.

Because heparin is required for FGF binding to its receptor, the interactions between FGF and sucrose octasulfate, a heparin analog, have been studied. The crystal structure of the complex between aFGF and sucrose octasulfate has been determined to 2.7 Å resolution by a combination of MIR and molecular replacement methods. Sucrose octasulfate binds to the aFGF positive patch mentioned above as a potential heparin binding site. Based on the structure of aFGF and sucrose octasulfate complex, a possible FGF receptor binding mechanism in the presence of heparin is proposed.

Other crystallographic studies of FGF include the structural determination of the two FGF mutants; the complex of aFGF and 1,3,6-naphthalene trisulfonate, a close analog of the FGF inhibitor suramin; and the bFGF-copper complex.

Item Type:Thesis (Dissertation (Ph.D.))
Subject Keywords:Chemistry
Degree Grantor:California Institute of Technology
Division:Chemistry and Chemical Engineering
Major Option:Chemistry
Thesis Availability:Public (worldwide access)
Research Advisor(s):
  • Rees, Douglas C.
Thesis Committee:
  • Unknown, Unknown
Defense Date:16 February 1993
Record Number:CaltechTHESIS:01102013-134402009
Persistent URL:https://resolver.caltech.edu/CaltechTHESIS:01102013-134402009
Default Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:7392
Collection:CaltechTHESIS
Deposited By: John Wade
Deposited On:10 Jan 2013 22:12
Last Modified:02 Dec 2020 02:16

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