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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.
Submitted August 1, 2003
Accepted November 4, 2003
Identification of a binding site on human FGF-2 for fibrinogen
Hu Peng, Abha Sahni, Philip J Fay, Stephen Bellum, Igor Prudovsky, Thomas Maciag, and Charles W Francis*
Department of Medicine, Hematology/Oncology Unit, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA
Center for Molecular Medicine, Maine Medical Center, Bethesda, ME, USA
* Corresponding author; email: charles_francis{at}urmc.rochester.edu.
Endothelial cell adhesive interactions are mediated by both fibrinogen and fibrin, and growth is stimulated by 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 five residues (Phe 95, Ser 100, Asn 102, Arg 107 and Arg 109) from FGF-2 into the corresponding sites in the third cassette of FGF-1 imparted high affinity binding with apparent Kd = 5.3nM and 8.6nM, respectively, compared to 1.3nM for wild-type FGF-2. We conclude that these five residues define a high affinity binding site in FGF-2 for fibrinogen.
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