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A dimeric ternary complex of FGFR [correction of FGFR1], heparin and FGF-1 leads to an 'electrostatic sandwich' model for heparin binding.
MedLine Citation:
PMID:  10404599     Owner:  NLM     Status:  MEDLINE    
BACKGROUND: Fibroblastic growth factors (FGFs) are a family of cytokines involved in regulation of cell growth, differentiation and chemotaxis in a variety of tissue types. High-affinity FGF receptors (FGFRs) are transmembrane proteins that consist of three extracellular immunoglobulin-like domains, a transmembrane helix and an intracellular protein tyrosine kinase signalling domain. FGFRs are activated through ligand-dependent dimerization that allows trans-autophosphorylation of the tyrosine kinase domains. Heparin or heparin-like molecules, such as heparan sulphate proteoglycans, bind to both FGFs and FGFRs and are required for FGF signal transduction. At present no structure of the ternary complex for FGFR, FGF and heparin exists.
RESULTS: We have used the type-1 interleukin-1 receptor-interleukin-1 beta complex crystal structure, in which both the ligand and the receptor are homologous to those of the FGF-FGFR pair, to identify potential interactions in the FGFR-heparin-FGF ternary complex. A key feature of the modelled complex is the 'electrostatic sandwich' that is formed between the positively charged surfaces of FGF and the receptor, with the negatively charged heparin captured in between. The ternary complex places limits on the range of likely modes of receptor dimerization: one of five different dimeric receptor complexes built from the ternary complex correlates best with the experimental data.
CONCLUSIONS: The ternary complex of FGFR, FGF and heparin, derived on the basis of the homologous interleukin-1 receptor complex, is in agreement with much of the published experimental data, as is the dimeric receptor complex (FGFR-heparin-FGF)2. This work suggests that the FGF interactions seen in crystal structures, which have previously been used to predict the mode of FGF dimerization, might not be relevant to the biologically active dimeric FGFR-heparin-FGF complex.
M T Huhtala; O T Pentikäinen; M S Johnson
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Structure (London, England : 1993)     Volume:  7     ISSN:  0969-2126     ISO Abbreviation:  Structure     Publication Date:  1999 Jun 
Date Detail:
Created Date:  1999-08-31     Completed Date:  1999-08-31     Revised Date:  2012-06-05    
Medline Journal Info:
Nlm Unique ID:  101087697     Medline TA:  Structure     Country:  ENGLAND    
Other Details:
Languages:  eng     Pagination:  699-709     Citation Subset:  IM    
Department of Biochemistry and Pharmacy, Abo Akademi University, Turku, Finland.
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MeSH Terms
Amino Acid Sequence
Heparin / chemistry*
Interleukin-1 / chemistry
Models, Molecular
Molecular Sequence Data
Muscle Proteins / chemistry
Myosin-Light-Chain Kinase
Peptide Fragments
Protein Binding
Protein Conformation
Receptor Protein-Tyrosine Kinases / chemistry*
Receptor, Fibroblast Growth Factor, Type 1
Receptor, Fibroblast Growth Factor, Type 4
Receptors, Fibroblast Growth Factor / chemistry*
Receptors, Interleukin-1 / chemistry
Sequence Alignment
Static Electricity
Reg. No./Substance:
0/Interleukin-1; 0/Muscle Proteins; 0/Peptide Fragments; 0/Peptides; 0/Receptors, Fibroblast Growth Factor; 0/Receptors, Interleukin-1; 0/telokin; 9005-49-6/Heparin; EC protein, human; EC protein, human; EC Protein-Tyrosine Kinases; EC, Fibroblast Growth Factor, Type 1; EC, Fibroblast Growth Factor, Type 4; EC Kinase
Erratum In:
Structure Fold Des 1999 Aug 15;7(8):R198

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