Structure-function studies of fibroblast growth factors (FGFS)
<p>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 deter...
| Main Author: | |
|---|---|
| Format: | Others |
| Language: | en |
| Published: |
1993
|
| Online Access: | https://thesis.library.caltech.edu/7392/2/Zhu_x_1993.pdf Zhu, Xiaotian (1993) Structure-function studies of fibroblast growth factors (FGFS). Dissertation (Ph.D.), California Institute of Technology. doi:10.7907/d0f2-e676. https://resolver.caltech.edu/CaltechTHESIS:01102013-134402009 <https://resolver.caltech.edu/CaltechTHESIS:01102013-134402009> |
| Summary: | <p>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.</p>
<p>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.</p>
<p>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.</p>
<p>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.</p>
|
|---|