ArticleMolecular and cellular biology2001
Identification of receptor and heparin binding sites in fibroblast growth factor 4 by structure-based mutagenesis.
Article in Molecular and cellular biology, 2001. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Who cites it
25 citing papers in PubMed, 66 citations in OpenAlex.
- Biallelic FGF4 Variants Linked to Thoracic Dystrophy and Respiratory Insufficiency.Clinical genetics · 2025Article
- Fibroblast Growth Factors: Roles and Emerging Therapeutic Applications.Current drug targets · 2025Review
- Enhancement of hMSC In Vitro Proliferation by Surface Immobilization of a Heparin-Binding Peptide.Molecules (Basel, Switzerland) · 2023Article
- In-Silico Analysis of Deleterious SNPs ofLife (Basel, Switzerland) · 2022Article
- FGF4, A New Potential Regulator in Gestational Diabetes Mellitus.Frontiers in pharmacology · 2022Article
- Structural Biology of the FGF7 Subfamily.Frontiers in genetics · 2019Review
- Combination of Heparin Binding Peptide and Heparin Cell Surface Coatings for Mesenchymal Stem Cell Spheroid Assembly.Bioconjugate chemistry · 2018Article
- Cell number and chondrogenesis in human mesenchymal stem cell aggregates is affected by the sulfation level of heparin used as a cell coating.Journal of biomedical materials research. Part A · 2016Article
- Heparin binding preference and structures in the fibroblast growth factor family parallel their evolutionary diversification.Open biology · 2016Article
- Interactions of signaling proteins, growth factors and other proteins with heparan sulfate: mechanisms and mysteries.Connective tissue research · 2015Review
- Transcriptional targets of Foxd3 in murine ES cells.Stem cell research · 2014Article
- Selecting antagonistic antibodies that control differentiation through inducible expression in embryonic stem cells.Proceedings of the National Academy of Sciences of the United States of America · 2013Article
- Molecular mechanisms of fibroblast growth factor signaling in physiology and pathology.Cold Spring Harbor perspectives in biology · 2013Review
- Fractone-heparan sulphates mediate FGF-2 stimulation of cell proliferation in the adult subventricular zone.Cell proliferation · 2013Article
- The structural biology of the FGF19 subfamily.Advances in experimental medicine and biology · 2012Review
- Influence of heparin mimetics on assembly of the FGF.FGFR4 signaling complex.The Journal of biological chemistry · 2010Article
- Differential interactions of FGFs with heparan sulfate control gradient formation and branching morphogenesis.Science signaling · 2009Article
- Molecular insights into the klotho-dependent, endocrine mode of action of fibroblast growth factor 19 subfamily members.Molecular and cellular biology · 2007Article
- Multimers of the fibroblast growth factor (FGF)-FGF receptor-saccharide complex are formed on long oligomers of heparin.The Biochemical journal · 2006Article
- Fibroblast growth factors share binding sites in heparan sulphate.The Biochemical journal · 2005Article
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Authors and funding
6 authors at 1 institution in 1 country.
Funding
Abstract
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.
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