TI  - Identification of residues important both for primary receptor binding and
      specificity in <prot>fibroblast growth factor-7</prot>.
PG  - 34881-6
AB  -  Fibroblast growth factors (FGFs) mediate a multitude of physiological and
      pathological processes by activating a family of tyrosine kinase receptors
       (FGFRs) . Each  FGFR  binds to a unique subset of  FGFs  and ligand binding
      specificity is essential in regulating FGF activity. <prot>FGF-7</prot>  recognizes one
      FGFR isoform known as the    <prot>FGFR2 IIIb</prot>  isoform or  <prot><prot>keratinocyte growth factor</prot> receptor</prot> (<prot>KGFR</prot>) , whereas <prot>FGF-2</prot>    binds well to  <prot>FGFR1</prot> ,  <prot>FGFR2</prot> , and  <prot>FGFR4</prot> but
      interacts poorly with <prot>KGFR</prot>. Previously, mutations in <prot>FGF-2</prot> identified a
      set of residues that are important for high affinity receptor binding,
      known as the primary receptor-binding site. <prot>FGF-7</prot> contains this primary
      site as well as a region that restricts interaction with <prot>FGFR1</prot>. The
      sequences that confer on <prot>FGF-7</prot> its specific binding to <prot>KGFR</prot> have not been
      identified. By utilizing domain swapping and site-directed mutagenesis we
      have found that the loop connecting the beta4-beta5 strands of <prot>FGF-7</prot>
      contributes to high affinity receptor binding and is critical for <prot>KGFR</prot>
      recognition. Replacement of this loop with the homologous loop from <prot>FGF-2</prot>
      dramatically reduced both the affinity of <prot>FGF7</prot>  for  <prot>KGFR</prot>  and its
      biological potency but did not result in the ability to bind <prot>FGFR1</prot>. Point
      mutations in residues comprising this loop of <prot>FGF-7</prot> reduced both binding
      affinity and biological potency. The reciprocal loop replacement mutant
      (<prot>FGF2</prot>-L4/7) retained   <prot>FGF-2</prot>   like affinity for  <prot>FGFR1</prot>  and for  <prot>KGFR</prot> . Our
      results show that topologically similar regions in these two FGFs have
      different roles in regulating receptor binding specificity and suggest
      that specificity may require the concerted action of distinct regions of
      an FGF.
AD  - Department of Biology and Department of Chemistry, Technion-Israel
