1ijt

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spinqualitylabelsall models 1ijt, resolution 1.80Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

Crystal Structure of Fibroblast Growth Factor 4 (FGF4)

Contents 1 Overview 2 Disease 3 About this Structure 4 Reference

Overview

Fibroblast growth factors (FGFs) comprise a large family of, multifunctional, heparin-binding polypeptides that show diverse patterns, of interaction with a family of receptors (FGFR1 to -4) that are subject, to alternative splicing. FGFR binding specificity is an essential, mechanism in the regulation of FGF signaling and is achieved through, primary sequence differences among FGFs and FGFRs and through usage of two, alternative exons, IIIc and IIIb, for the second half of, immunoglobulin-like domain 3 (D3) in FGFRs. While FGF4 binds and activates, the IIIc splice forms of FGFR1 to -3 at comparable levels, it shows little, activity towards the IIIb splice forms of FGFR1 to -3 as well as towards, FGFR4. To begin to explore the structural determinants for this, differential affinity, we determined the crystal structure of FGF4 at a, 1.8-A resolution. FGF4 adopts a beta-trefoil fold similar to other FGFs., To identify potential receptor and heparin binding sites in FGF4, a, ternary FGF4-FGFR1-heparin model was constructed by superimposing the FGF4, structure onto FGF2 in the FGF2-FGFR1-heparin structure. Mutation of, several key residues in FGF4, observed to interact with FGFR1 or with, heparin in the model, produced ligands with reduced receptor binding and, concomitant low mitogenic potential. Based on the modeling and mutational, data, we propose that FGF4, like FGF2, but unlike FGF1, engages the, betaC'-betaE loop in D3 and thus can differentiate between the IIIc and, IIIb splice isoforms of FGFRs for binding. Moreover, we show that FGF4, needs to interact with both the 2-O- and 6-O-sulfates in heparin to exert, its optimal biological activity.

Disease

Known disease associated with this structure: Histidinemia OMIM:[609457]

About this Structure

1IJT is a Single protein structure of sequence from Homo sapiens with as ligand. Full crystallographic information is available from OCA.

Reference

Identification of receptor and heparin binding sites in fibroblast growth factor 4 by structure-based mutagenesis., Bellosta P, Iwahori A, Plotnikov AN, Eliseenkova AV, Basilico C, Mohammadi M, Mol Cell Biol. 2001 Sep;21(17):5946-57. PMID:11486033

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