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PEDS Advance Access published online on October 6, 2004
Protein Engineering Design and Selection, doi:10.1093/protein/gzh076
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Received April 9, 2004
Revised September 15, 2004
Accepted September 16, 2004

Article

Design of fully active FGF-1 variants with increased stability

Malgorzata Zakrzewska 1, Daniel Krowarsch 1, Antoni Wiedlocha 2, and Jacek Otlewski 1*

1 Institute of Biochemistry and Molecular Biology, University of Wroclaw, Tamka 2, 50-137 Wroclaw, Poland
2 Department of Biochemistry, Institute for Cancer Research, The Norwegian Radium Hospital, N-0310 Oslo, Norway

* To whom correspondence should be addressed. E-mail: otlewski{at}protein.pl.


  Abstract

Fibroblast growth factor 1 is a powerful mitogen playing an important role in morphogenesis, angiogenesis, wound healing and is therefore of potential medical interest. Using homologous sequence and structure comparisons we designed and constructed 16 mutants of FGF-1 with increased thermodynamic stability, as determined by chemical and temperature denaturation. For multiple mutants additive effects on stability were observed, providing mutants up to 7.8°C more stable than the wild-type. All introduced mutations did not affect any of FGF-1 biological activities, such as stimulation of DNA synthesis, MAP kinase activation and binding to the FGF receptor on the cell surface. Our study provide a good starting point to improve the stability of FGF-1 in context of its wide potential therapeutic applications. We showed that homology approach is an effective method to change thermodynamic properties of the protein without altering its function.

Keywords: fibroblast growth factor; protein engineering; stability; DNA synthesis; MAP kinase activation.
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M. Zakrzewska, A. Wiedlocha, A. Szlachcic, D. Krowarsch, J. Otlewski, and S. Olsnes
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