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Blood, 15 March 2004, Vol. 103, No. 6, pp. 2114-2120.
Prepublished online as a Blood First Edition Paper on November 20, 2003; DOI 10.1182/blood-2003-08-2638.
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HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY
Identification of a binding site on human FGF-2 for fibrinogen
Hu Peng,
Abha Sahni,
Philip Fay,
Stephen Bellum,
Igor Prudovsky,
Thomas Maciag, and
Charles W. Francis
From the Department of Medicine, Hematology/Oncology Unit, University of Rochester School of Medicine and Dentistry, Rochester, NY; and the Center for Molecular Medicine, Maine Medical Center Research Institute, Scarborough, ME.
Endothelial cell adhesive interactions are mediated by both fibrinogen and fibrin, and growth is stimulated by fibroblast growth factor 2 (FGF-2). We have shown previously that FGF-2 binds specifically and with high affinity to fibrinogen and fibrin and that fibrinogen potentiates the proliferative capacity of FGF-2 and also protects it from proteolytic degradation. To further characterize this interaction we have performed FGF-2 mutagenesis to identify the interactive site. Because FGF-1 has a similar structure to FGF-2 but does not bind to fibrinogen, we used a strategy of cassette and site-directed mutagenesis, exchanging residues from FGF-1 and FGF-2 and correlating structural changes with fibrinogen binding. Two cassette interchange mutants, 2212 and 2211, contained either the third cassette or both the third and fourth cassettes from FGF-1, and neither exhibited any affinity for fibrinogen. Exchange of 5 residues (Phe95, Ser100, Asn102, Arg107, and Arg109) from FGF-2 into the corresponding sites in the third cassette of FGF-1 imparted high-affinity binding with apparent dissociation constants (Kd) of 5.3 nM and 8.6 nM, respectively, compared with 1.3 nM for wild-type FGF-2. We conclude that these 5 residues define a high-affinity binding site in FGF-2 for fibrinogen.
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