Crystal Structure of Basic Fibroblast Growth Factor at 1.6 Å Resolution

Ago, Hideo; Kitagawa, Y.; Fujishima, Akira; Matsuura, Yoshiki; Katsube, Yukiteru

doi:10.1093/oxfordjournals.jbchem.a123586

Cited by 84 publications

(59 citation statements)

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“…For FGF2, the crystal structure with the highest resolution (PDB code 1bgf) showed disorder for the ®rst 19±20 N-terminal residues (Ago et al, 1991), con®rmed by NMR studies of complete FGF2 (PDB code 1rml), which showed disorder for the N-terminal 28 residues (Moy et al, 1996). For FGF1 the crystal structure with the highest resolution (PDB code 2afg) showed disorder for the N-terminal 9±10 residues (Blaber et al, 1996); for the NMR structure (PDB code 1rml) a molecule N-terminally truncated at residue 25 was used (Lozano et al, 1998).…”

Section: Acta Cryst (2001) D57 378±384mentioning

confidence: 99%

Structure of fibroblast growth factor 9 shows a symmetric dimer with unique receptor- and heparin-binding interfaces

Hecht¹,

Adar

Hofmann³

et al. 2001

Acta Crystallogr D Biol Cryst

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Fibroblast growth factors (FGFs) constitute a family of at least 20 structurally related heparin-binding polypeptides active in regulating cell growth, survival, differentiation and migration. FGF9, originally discovered as a glia-activating factor, shares 30% sequence identity with other FGFs and has a unique spectrum of target-cell speci®city. FGF9 crystallized in the tetragonal space group I4 1 , with unit-cell parameters a = b = 151.9, c = 117.2 A Ê . The structure of the glycosylated protein has been re®ned to an R value of 21.0% with R free = 24.8%) at 2.6 A Ê resolution. The four molecules in the asymmetric unit are arranged in two non-crystallographic dimers, with the dimer interface composed partly of residues from N-and C-terminal extensions from the FGF core structure. Most of the receptor-binding residues identi®ed in FGF1± and FGF2±receptor complexes are buried in the dimer interface, with the 8± 9 loop stabilized in a particular conformation by an intramolecular hydrogen-bonding network. The potential heparin-binding sites are in a pattern distinct from FGF1 and FGF2. The carbohydrate moiety attached at Asn79 has no structural in¯uence.

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Section: Acta Cryst (2001) D57 378±384mentioning

confidence: 99%

Structure of fibroblast growth factor 9 shows a symmetric dimer with unique receptor- and heparin-binding interfaces

Hecht¹,

Adar

Hofmann³

et al. 2001

Acta Crystallogr D Biol Cryst

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“…These assignments have led to the determination of the solution secondary structure for FGF-2, based on NOE data involving the NH, H α , and H β protons as well as 3 JH N H α coupling constants, amide exchange, and 13 C α and 13 C β secondary chemical shifts. Two crystal structures have been reported for FGF-2, where the protein is described as a β-sheet barrel of six antiparallel β-strands with a base of six additional β-strands (Zhu et al, 1983;Ago et al, 1991;Eriksson et al, 1991;Zhang et al, 1991). Comparison between the NMR secondary structure and the refined X-ray structure indicates clearly similar structures; however, some distinct differences exist, particularly at the heparin-binding site.…”

Section: Introductionmentioning

confidence: 99%

1H, 15N, 13C and 13CO assignments and secondary structure determination of basic fibroblast growth factor using 3D heteronuclear NMR spectroscopy

et al. 1995

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Supplementary material-tables containing the 1 H, 15 N, 13 CO, and 13 C resonance assignments for the major and minor conformations of FGF-2-is available in the Biological Magnetic Resonance Data Bank, BMRB 4091, at http://www.bmrb.wisc.edu/data_library/summary/index.php?bmrbId=4091. AbstractThe assignments of the 1 H, 15 N, 13 CO, and 13 C resonances of recombinant human basic fibroblast growth factor (FGF-2), a protein comprising 154 residues and with a molecular mass of 17.2 kDa, is presented based on a series of three-dimensional triple-resonance heteronuclear NMR experiments. These studies employ uniformly labeled 15 N-and 15 N-/ 13 C-labeled FGF-2 with an isotope incorporation > 95% for the protein expressed in E. coli. The sequence-specific backbone assignments were based primarily on the interresidue correlation of C α , C β , and H α to the backbone amide 1 H and 15 N of the next residue in the CBCA(CO)NH and HBHA(CO)NH experiments and the intraresidue correlation of C α , C β , and H α to the backbone amide 1 H and 15 N in the CBCANH and HNHA experiments. In addition, C α and C β chemical shift assignments were used to determine amino acid types. Sequential assignments were verified from carbonyl correlations observed in the HNCO and2 HCACO experiments and C α correlations from the HNCA experiment. Aliphatic side-chain spin systems were assigned primarily from H(CCO)NH and C(CO)NH experiments that correlate all the aliphatic 1 H and 13 C resonances of a given residue with the amide resonance of the next residue. Additional side-chain assignments were made from HCCH-COSY and HCCH-TOCSY experiments. The secondary structure of FGF-2 is based on NOE data involving the NH, H α , and H β protons as well as 3 JH N H α coupling constants, amide exchange, and 13 C α and 13 C β secondary chemical shifts. It is shown that FGF-2 consists of 11 well-defined antiparallel β-sheets (residues 30-34, 39-44, 48-53, 62-67, 71-76, 81-85, 91-94, 103-108, 113-118, 123-125, and 148-152) and a helix-like structure (residues 131-136), which are connected primarily by tight turns. This structure differs from the refined X-ray crystal structures of FGF-2, where residues 131-136 were defined as β-strand XI. The discovery of the helix-like region in the primary heparin-binding site (residues 128-138) instead of the β-strand conformation described in the X-ray structures may have important implications in understanding the nature of heparin-FGF-2 interactions. In addition, two distinct conformations exist in solution for the N-terminal residues 9-28. This is consistent with the X-ray structures of FGF-2, where the first 17-19 residues were ill defined.

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“…This region forms a compact (3-barrel with 3-fold symmetry that is nearly identical in structure to the folded core of interleukins-la and -13 (18)(19)(20)(21). FGF-1 and FGF-2 also resemble interleukin-1,B in lacking a classical signal sequence.…”

mentioning

confidence: 99%

Fibroblast growth factor (FGF) homologous factors: new members of the FGF family implicated in nervous system development.

Smallwood

Muñoz-Sanjuán

Tong

et al. 1996

Proc. Natl. Acad. Sci. U.S.A.

366

306

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Four new members of the fibroblast growth factor (FGF) family, referred to as fibroblast growth factor homologous factors (FHFs), have been identified by a combination of random cDNA sequencing, data base searches, and degenerate PCR. Pairwise comparisons between the four FHFs show between 58% and 71% amino acid sequence identity, but each FHF shows less than 30%o identity when compared with other FGFs. Like FGF-1 (acidic FGF) and FGF-2 (basic FGF), the FHFs lack a classical signal sequence and contain clusters of basic residues that can act as nuclear localization signals. In transiently transfected 293 cells FHF-1 accumulates in the nucleus and is not secreted. Each FHF is expressed in the developing and adult nervous systems, suggesting a role for this branch of the FGF family in nervous system development and function.Fibroblast growth factors (FGFs) comprise a family of nine related polypeptides with broad mitogenic and cell survival activities (1-3). FGF-1 (acidic FGF) and FGF-2 (basic FGF), the first family members to be identified, purified, and sequenced, are widely expressed and are potent mitogens for a variety of cell types (4, 5). The gene encoding FGF-3 is a common target for activation by the mouse mammary tumor virus (6), and the genes encoding FGF-4, have transforming activity when introduced into NIH 3T3 cells (7-9). FGF-7, FGF-8, and FGF-9 are mitogens for keratinocytes, mammary carcinoma cells, and astrocytes, respectively (10-12). Recent experiments indicate that several FGFs have bioactivities that were not evident during their initial identification. For example, FGF-2 can induce ventral mesoderm in Xenopus embryos (13,14), FGF-4 is involved in growth and patterning of the chicken limb bud (15), FGF-5 controls hair follicle cycling in the mouse (16), and FGF-8 can cause duplications of the embryonic chicken midbrain (17).The nine known FGFs are between 155 and 268 amino acid residues in length and share a conserved central region of -140 amino acids. This region forms a compact (3-barrel with 3-fold symmetry that is nearly identical in structure to the folded core of interleukins-la and -13 (18-21). FGF-1 and FGF-2 also resemble interleukin-1,B in lacking a classical signal sequence. Current data indicate that FGF-1 and FGF-2 are released from cells by a route that is distinct from the endoplasmic reticulum-Golgi secretory pathway (22, 23).FGF signaling is generally assumed to occur by activation of transmembrane tyrosine kinase receptors. Four FGF receptor (FGFR) genes have been identified thus far (24), and activating or inactivating receptor mutations have been described for a subset of these genes in both mice and humans. In the mouse, disruption of the FGFR1 or FGFR2 genes leads to early embryonic lethality (25,26), and disruption of FGFR3 leads to bone overgrowth (27,28). In humans, point mutations in FGFR1, FGFR2, and FGFR3 have been found in a variety of skeletal disorders (reviewed in ref. 29).In this paper we report the identification and characterization of four new mem...

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Crystal Structure of Basic Fibroblast Growth Factor at 1.6 Å Resolution

Cited by 84 publications

References 0 publications

Structure of fibroblast growth factor 9 shows a symmetric dimer with unique receptor- and heparin-binding interfaces

Structure of fibroblast growth factor 9 shows a symmetric dimer with unique receptor- and heparin-binding interfaces

1H, 15N, 13C and 13CO assignments and secondary structure determination of basic fibroblast growth factor using 3D heteronuclear NMR spectroscopy

Fibroblast growth factor (FGF) homologous factors: new members of the FGF family implicated in nervous system development.

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