Year-end Sale % OFF 
Abstract
Members of the fibroblast growth factor (FGF) family promote angiogenesis and wound repair, modulate early developmental events and survival of neurons, and have been associated with the pathogenesis of various diseases. FGFs interact with specific FGF receptors (FGFRs) and heparan sulfate proteoglycans on cell surfaces to mediate mitogenesis. Using protein structure-based site-directed mutagenesis of basic FGF (bFGF), we have identified two FGFR binding sites on bFGF which act in concert to initiate signal transduction. Both FGFR binding surfaces are distinct from the heparan sulfate proteoglycan binding domain. The primary, higher affinity, binding interaction comprises a cluster of solvent exposed hydrophobic amino acids (Tyr-24, Tyr-103, Leu-140, and Met-142), and two polar residues (Arg-44 and Asn-101). The hydrophobic contacts dominate the primary binding interaction and provide approximately 75% of the binding affinity. The secondary FGFR binding site on bFGF has an approximately 250-fold lower affinity and is composed of amino acids Lys-110, Tyr-111, and Trp-114 in a surface-exposed type I beta-turn (formerly known as the putative receptor binding loop). Binding of FGFR to both bFGF surfaces in a stoichiometry of 2FGFR:1bFGF is required for growth factor mediated cell proliferation. This represents a mechanism for the fibroblast growth factor/receptor family in which FGF facilitates FGFR dimerization and subsequent signal transduction events as a monomeric ligand.
Highlights
From the Departments of $Crystallography and Biophysical Chemistry, llCardiovascular Disease Research, and §§Biotechnology, DuPont Merck Pharmaceutical Company, DuPont Experimental Station, Wilmington, Delaware 19880-0228
Using protein structure- Members of the FGFfamily are known to interacton cell surbased site-directed mutagenesis of basic fibroblast growth factor (FGF), faces with bothspecific FGF receptors (FGFR) and heparan sul
Several mechanisms havebeen proposed to explain the concerted role of FGF and heparin iFnGF/FGFR interactions that initiate cell proliferative responses.Thefirstsuggeststhat FGF binds to HSPG and is either presentedor transferred to FGFR resulting in growth factor internalization and the initiation of cellular responses[19]
Summary
Several mechanisms havebeen proposed to explain the concerted role of FGF and heparin iFnGF/FGFR interactions that initiate cell proliferative responses.Thefirstsuggeststhat FGF binds to HSPG and is either presentedor transferred to FGFR resulting in growth factor internalization and the initiation of cellular responses[19]. 1and 2).Members of this family control the proliferamarily on published reports inwhich heparin binding to FGF was thought to be obligatory for FGFLFGFR binding interactions [11,20] This has been refutedrecently by both cell surface receptor binding experiments and binding measurements made using purified soluble FGFR [16,18].
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
