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Sequence swapping does not result in conformation swapping for the 4/5 and 8/9 -hairpin turns in human acidic fibroblast growth factor

Kasha Institute of Molecular Biophysics and Department of Chemistry and Biochemistry, Florida State University, Tallahassee, Florida 32306-4380, USA

(RECEIVED September 1, 2004; FINAL REVISION September 25, 2004; ACCEPTED September 27, 2004)

The -turn is the most common type of nonrepetitive structure in globular proteins, comprising ~25% of all residues; however, a detailed understanding of effects of specific residues upon -turn stability and conformation is lacking. Human acidic fibroblast growth factor (FGF-1) is a member of the -trefoil superfold and contains a total of five -hairpin structures (antiparallel -sheets connected by a reverse turn). -Turns related by the characteristic threefold structural symmetry of this superfold exhibit different primary structures, and in some cases, different secondary structures. As such, they represent a useful system with which to study the role that turn sequences play in determining structure, stability, and folding of the protein. Two turns related by the threefold structural symmetry, the 4/5 and 8/9 turns, were subjected to both sequence-swapping and poly-glycine substitution mutations, and the effects upon stability, folding, and structure were investigated. In the wild-type protein these turns are of identical length, but exhibit different conformations. These conformations were observed to be retained during sequence-swapping and glycine substitution mutagenesis. The results indicate that the -turn structure at these positions is not determined by the turn sequence. Structural analysis suggests that residues flanking the turn are a primary structural determinant of the conformation within the turn.

Keywords: -hairpin; fibroblast growth factor; folding kinetics; stability; turn conformation

Abbreviations: FGF-1, human acidic fibroblast growth factor • NOE, nuclear Overhauser effect • NOESY, nuclear Overhauser spectroscopy • HSQC, heteronuclear single quantum correlation • TROSY, transverse-relaxation optimized spectroscopy • TOCSY, total correlation spectroscopy • ADA, N-(2-acetamido)iminodiacetic acid • DTT, dithiothreitol • GuHCl, guanidinium hydrochloride • RT, room temperature (25°C) • FGFR, fibroblast growth factor receptor • the single-letter amino acid code is utilized in the description of FGF-1 mutations • r.m.s., root-mean-square

Article published online ahead of print. Article and publication date are at http://www.proteinscience.org/cgi/doi/10.1110/ps.041094205.

Reprint requests to: Michael Blaber, Kasha Institute of Molecular Biophysics, Florida State University, Tallahassee, FL 32306-4380, USA; e-mail: blaber{at}sb.fsu.edu; fax: (850) 644-7244.

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