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Protein Engineering, Vol. 15, No. 12, 1021-1024, December 2002
© 2002 Oxford University Press

Novel mutant human fibronectin FIII9–10 domain pair with increased conformational stability and biological activity

Christopher F. van der Walle, Harri Altroff1 and Helen J. Mardon2

Nuffield Department of Obstetrics and Gynaecology, University of Oxford, Women’s Centre, Level 3, John Radcliffe Hospital, Headington, Oxford OX3 9DU, UK

The ninth and tenth type III domains (FIII9–10) in the central cell binding domain of human fibronectin contain integrin receptor binding sites, including RGD in FIII10 and a synergy site, PHSRN, in FIII9. The specific amino acids that contribute to cell binding have been identified by the use of wild-type and mutant fragments of human fibronectin containing the FIII9–10 domain pair. At high concentrations FIII9–10 mimics, to a large extent, the biological activity of the full-length fibronectin molecule. However, FIII9 is conformationally unstable, even in the context of the FIII9–10 pair. Here we report the construction of a series of hybrid mouse–human FIII9–10 pairs that confer varying degrees of conformational stability to FIII9. The conformational stability of the human FIII9 module was increased 2–3-fold by substitution of Leu1408 with Pro. We demonstrate that the biological activity of this mutant is enhanced. The resulting FIII9–10 mutant has good solution properties and will provide a template into which further mutations can be incorporated in order to probe the structure–function relationship of the cell binding module of fibronectin.


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