FGF 7 Kinemages

The Rat Fibroblast Growth Factor 7

Larry P. Taylor, Ph. D.

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Email: lpt

Molecular & Behavioral Neuroscience Institute

The University of Michigan

Ann Arbor, MI

FGF 7 (also known as KFG for keratinocycte growth factor) is found in mesenchymal cells of parenchymal organs. It binds exclusively to a slice variant (IIIb) of the FGF Receptor 2 found in epithial cells. FGF 7 is more selective than FGF 1 and FGF 2 in binding to FGF receptors. Differences in sequence and geometry can rationalize this selectivity. A backbone comparison of FGF 7 overlaid upon FGF 2 is shown in Kinemage 6 .

The crystal structure for FGF 7 ( Kinemage 1 ) was determined on a protein engineered from the rat sequence. The Clustal X alignment of human and rat FGF 7 sequences is shown below: A single molecule of FGF 7 is shown in Kinemage 2. The secondary structure cartoon of FGF 7 is shown in Kinemage 3.

The residues, except Ser-105 (which is X-ray unresolved), that are different between human and rat are Arg-38 (to Lys), Ser-40 (to Asn), Tyr-63 (to Phe), Ser-105 (to Asn), Leu-118 (to Ile), and Lys-121 (to Arg). These residues are highlighted in Kinemage 4. The Arg-35 implicated in high affinity binding of FGF 1 and FGF 2 is a glutamine in FGF 7. The characteristics of the unit cell for this structure are summarized at pdbsum.

Of particular interest is the portion of the molecule that is associated with low affinity binding (receptor discrimination loop) in the vicinity of the residues 102-107. In the receptor unbound FGF 7 molecule, this region is unresolved. This suggests a conformational mobility (especially compared to FGF 1 and FGF 2) that may be important in FGF receptor discrimination. This low affinity loop region is also a few residues longer which would present an altered (compared to FGF 1 and FGF 2) binding geometry to a FGF receptor.

Although FGF 7 shows the FGF conserved "hydrophobic patch" (Phe-16, Tyr-22, Tyr-94, Leu-135, Met-137), there is an additional "hydrophobic ridge" (Val-120, Thr-125, and Thr-131) which separates the overall surface charge of the "basic canyon" (Kinemage 7) into two distinct regions. In FGF 7, the primary heparin binding residues (Arg-18, Asn-92, Asn-114, Gln-115, Lys-124, Gln-129, and Lys-130) are separated by this "hydrophobic ridge" .In addition, FGF residue Glu-128 places a negative charge in the heparin binding region (as defined by FGF 1 and FGF 2) which would impair approach of strongly anionic species. This suggests that heparins (a wide variety of negatively charged sulfated sugars) would bind FGF 7 with a different geometry than binding to FGF 1 or FGF 2. The altered pattern of the heparin binding domain is most likely a strong factor in its specificity since the growth factor-heparin complex is a component of growth factor binding to its receptors. The hydrophobic patch is highlighted in Kinemage 5 .

Space filling images (with the "basic canyon" surrounded by a yellow box) showing a front and side view comparison are shown below. Basic residues are blue; acidic residues are red; hydrophobics are green; neutral polar residues are orange; hydrogen atoms are cyan and the peptide backbone is white.

Note the difference in the pattern of the positively charged (blue) and hydrophobic (green) residues.

The real-time visualization using KiNG of the structures on this site requires a java-enabled (JRE from Java) browser.

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Click On KiNG to see	Calpha Trace of FGF 7 Unit Cell

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Click On KiNG to see	Ribbon Rendering of FGF 7

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Click On KiNG to see	Cartoon Rendering of FGF 7

The residues, except Ser-105 (which is X-ray unresolved), that are different between human and rat are Arg-38 (to Lys), Ser-40 (to Asn), Tyr-63 (to Phe), Ser-105 (to Asn), Leu-118 (to Ile), and Lys-121 (to Arg). The Arg-35 implicated in high affinity binding of FGF 1 and FGF 2 is a glutamine in FGF 7.

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Click On KiNG to see	Residues Different In Human Sequence

The "hydrophobic patch" consists of residues Phe-16, Tyr-22, Tyr-94, Leu-135, and Met-137. Additional residues associated with binding (Gln-35 and Asn-92) are also shown.

View 1 FGF 7 monomer with binding residues highlighted
View 2 the "hydrophobic" patch of the high affinity binding region
View 3 the conserved Asn residue of the low affinity loop

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Click On KiNG to see	The "Hydrophobic Patch"

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Click On KiNG to see	Calpha Trace of FGF 7 Superimposed on FGF 2

The overlay of FGF 7 upon FGF 2 with "basic canyon" residues (Arg-18, Asn-92, Asn-114, Gln-115, Lys-124, Gln-129, and Lys-130) highlighted Also shown are those FGF 7 residues which would diminish or alter heparin binding (Hydrophobics: Val-120, Thr-125, and Thr-131 and negatively charged: Glu-128).

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Click On KiNG to see	Comparison of "Basic Canyon" of FGF 2 and FGF 7

X-Ray Resolved: DIRVRRLFCRTQWYLRIDKRGKVKGTQEMRNSYNIMEIRTVA
VGIVAIKGVESEYYLAMNKEGKLYAKKECNEDCNFKELILENHYNTYASAKW

SYDYMEGGDIRVRRLFCRTQWYLRIDKRGKVKGTQEMKNNYNIMEIRTVAVGIVAIKG
VESEFYLAMNKEGKLYAKKECNEDCNFKELILENHYNTYASAKWTHNGGEMFVALNQK
GIPVRGKKTKKEQKTAHFLPMAIT

The rat FGF sequence was expressed in e.coli; The structural coordinates were taken from Brookhaven Database file 1QQK.