Spackling the crack: stabilizing human fibroblast growth factor-1 by targeting the N and C terminus beta-strand interactions

J Mol Biol. 2007 Aug 3;371(1):256-68. doi: 10.1016/j.jmb.2007.05.065. Epub 2007 May 31.


The beta-trefoil protein human fibroblast growth factor-1 (FGF-1) is made up of a six-stranded antiparallel beta-barrel closed off on one end by three beta-hairpins, thus exhibiting a 3-fold axis of structural symmetry. The N and C terminus beta-strands hydrogen bond to each other and their interaction is postulated from both NMR and X-ray structure data to be important in folding and stability. Specific mutations within the adjacent N and C terminus beta-strands of FGF-1 are shown to provide a substantial increase in stability. This increase is largely correlated with an increased folding rate constant, and with a smaller but significant decrease in the unfolding rate constant. A series of stabilizing mutations are subsequently combined and result in a doubling of the DeltaG value of unfolding. When taken in the context of previous studies of stabilizing mutations, the results indicate that although FGF-1 is known for generally poor thermal stability, the beta-trefoil architecture appears capable of substantial thermal stability. Targeting stabilizing mutations within the N and C terminus beta-strand interactions of a beta-barrel architecture may be a generally useful approach to increase protein stability. Such stabilized mutations of FGF-1 are shown to exhibit significant increases in effective mitogenic potency, and may prove useful as "second generation" forms of FGF-1 for application in angiogenic therapy.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Crystallography, X-Ray
  • Fibroblast Growth Factor 1 / chemistry*
  • Fibroblast Growth Factor 1 / genetics
  • Fibroblast Growth Factor 1 / metabolism
  • Humans
  • Models, Molecular
  • Molecular Sequence Data
  • Protein Denaturation
  • Protein Folding
  • Protein Structure, Secondary*
  • Protein Structure, Tertiary*
  • Thermodynamics


  • Fibroblast Growth Factor 1