title: Oligomerization of acidic fibroblast growth factor is not a prerequisite for its cell proliferation activity.
abstract: Oligomerization of fibroblast growth factors (FGFs) induced on binding to heparin or heparan sulfate proteoglycan is considered to be crucial for receptor activation and initiation of biological responses. To gain insight into the mechanism of activation of the receptor by FGFs, in the present study we investigate the effect(s) of interaction of a heparin analog, sucrose octasulfate (SOS), on the structure, stability, and biological activities of a recombinant acidic FGF from Notophthalmus viridescens (nFGF-1). SOS is found to bind to nFGF-1 and significantly increase the thermodynamic stability of the protein. Using a variety of techniques such as size-exclusion chromatography, sedimentation velocity, and multidimensional nuclear magnetic resonance (NMR) spectroscopy, it is shown that binding of SOS to nFGF-1 retains the protein in its monomeric state. In its monomeric state (complexed to SOS), n-FGF-1 shows significant cell proliferation activity. (15)N and (1)H chemical shift perturbation and the intermolecular nuclear Overhauser effects (NOEs) between SOS and nFGF-1 reveal that the ligand binds to the dense, positively charged cluster located in the groove enclosed by beta-strands 10 and 11. In addition, molecular modeling based on the NOEs observed for the SOS-nFGF-1 complex, indicates that SOS and heparin share a common binding site on the protein. In conclusion, the results of the present study clearly show that heparin-induced oligomerization of nFGF-1 is not mandatory for its cell proliferation activity.
authors.affiliation: Department of Chemistry, National Tsing Hua University, Hsinchu, Taiwan.
authors.forename: Alphonse I
authors.initials: AI
authors.lastname: Arunkumar
authors.forename: Thallampuranam Krishnaswamy S
authors.initials: TK
authors.lastname: Kumar
authors.forename: Karuppanan Muthusamy
authors.initials: KM
authors.lastname: Kathir
authors.forename: Sampath
authors.initials: S
authors.lastname: Srisailam
authors.forename: Han-Min
authors.initials: HM
authors.lastname: Wang
authors.forename: Philominathan Sagaya Theresa
authors.initials: PS
authors.lastname: Leena
authors.forename: Ya-Hui
authors.initials: YH
authors.lastname: Chi
authors.forename: Ho-Chz
authors.initials: HC
authors.lastname: Chen
authors.forename: Chieh-Hsi
authors.initials: CH
authors.lastname: Wu
authors.forename: Rong-Tsun
authors.initials: RT
authors.lastname: Wu
authors.forename: Gu-Gang
authors.initials: GG
authors.lastname: Chang
authors.forename: Ing-Ming
authors.initials: IM
authors.lastname: Chiu
authors.forename: Chin
authors.initials: C
authors.lastname: Yu
mesh_terms: D000818:Animals; D001665:Binding Sites; D002845:Chromatography; D016220:Fibroblast Growth Factor 1 / Q000737:chemistry* / Q000378:metabolism; D008934:Mitogens / Q000378:metabolism; D009673:Notophthalmus viridescens; D013395:Sucrose / Q000031:analogs & derivatives* / Q000378:metabolism
chemical_list: D008934:Mitogens; D016220:Fibroblast Growth Factor 1; D013395:Sucrose; C053081:sucrose octasulfate