Review
Role of heparan sulfate in fibroblast growth factor signalling: a structural view

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Abstract

Fibroblast growth factors (FGFs) are among the best-studied heparin-binding proteins, and heparan sulfate proteoglycans regulate FGF signalling by direct molecular association with FGF and its tyrosine kinase receptor, FGFR. Two recently determined crystal structures of FGF–FGFR–heparin complexes have provided new structural information on how heparin binds to FGF and FGFR, and lead to different models for receptor dimerisation.

Introduction

It is now accepted that heparan sulfate (HS) plays an essential role in fibroblast growth factor (FGF) signalling by direct association with FGF and FGF receptor (FGFR) in a ternary complex on the surface of the cell [1]. Understanding at atomic detail the precise mechanism by which HS regulates FGF signal transduction has aroused a great deal of interest. This stems from the importance of the physiological and pathological processes controlled by FGF, and the realisation that HS probably regulates the activity of many other signalling molecules. It is now ten years since the first crystal structure of an FGF ligand was solved [2], and five since publication of the first FGF–heparin complex [3]. The ongoing crystallographic efforts culminated with the recent determination of the crystal structures of two FGF–FGFR–heparin complexes 4••., 5••.. The structural information provided by these studies has been crucial in accurately mapping the mode of interaction of heparin with both FGF and FGFR, although uncertainty still remains as to how FGF and heparin/HS cooperate to dimerise the receptor.

The purpose of this review is twofold: firstly, to outline the features of the two crystallographic models and discuss their implications for the role of HS in FGF signalling; and secondly, to reassess the available structural data concerning the interaction of heparin with FGF and FGFR, with particular consideration of the role of the sulfate groups.

Section snippets

Description of current crystallographic models for the FGF–FGFR–heparin complex

In the crystal structure of FGF2 bound to the extracellular, ligand-binding region (immunoglobulin [Ig] domains D2 and D3) of FGFR1 [6], two binary FGF2–FGFR1 complexes interact by direct association of the receptor chains. This creates a deep, positively charged cleft that was proposed to represent the heparin/HS-binding site and implies a 2:2:1 FGF–FGFR–heparin complex. The stoichiometry was revised, however, to 2:2:2 on the basis of the structure of a complex formed by soaking the crystals

The 1:1:1 FGF–FGFR–heparin complex as an invariant component of the FGF signalling assembly

Although the two models differ in their proposed mechanism of FGFR dimerisation, they agree on one essential feature of the FGF signalling complex.,Within each model, it is possible to identify one FGF, one heparin molecule and the second Ig domain (D2) of one FGFR chain, constituting what can be termed the 1:1:1 FGF–FGFR–heparin complex (Fig. 1c). The relative spatial arrangement of its components, as well as their pairwise interactions, is, by and large, the same in the two models, except

Analysis of crystal lattice contacts in the crystals of the FGF1–FGFR2–heparin complex

A comparison of the two crystal structures shows that a modified version of the receptor–receptor contact forming the cleft described by Plotnikov et al. [6] is also present in the crystals of the FGF1–FGFR2–decamer complex [5••] (Fig. 1d). A further noncrystallographic twofold axis is generated by the 31 screw axis present as a result of the hexagonal symmetry of the crystals, leading to a similar dimer interaction. The decasaccharide, however, occupies only the entry to the cleft with its

Implications of the crystallographic models for HS function in FGF signalling

The distinguishing feature of the model put forward by Schlessinger et al. [4••] is the inclusion of two polysaccharide chains in the complex. On the surface of the cell, two 1:1 FGF–FGFR complexes would therefore form on separate HS chains; the arrangement of the two oligosaccharides in the crystallographic model, with their nonreducing ends facing each other, requires that the two binary complexes migrate to the free ends of the HS chain in order to promote FGFR dimerisation. Alternatively,

A structure-based proposal for an HS sequence able to bind FGF and FGFR

In an effort to analyse what is common and what is different in the mode of heparin binding to different FGFs and FGF–FGFR complexes, the available crystallographic models of FGF–heparin 3., 15. and FGF–FGFR–heparin 4••., 5••. complexes were overlaid and the protein–heparin contacts examined. Such an analysis revealed the following noteworthy features of the protein–heparin interaction in the FGF system (Fig. 2 Fig. 3).

Interactions between heparin and FGFR involve a single disaccharide at the

Conclusions and future directions

Crystallographic investigations of heparin bound to FGF or FGF–FGFR complexes have provided crucial insight into the mechanism of HS recognition. Future biochemical and cellular studies, together with careful biophysical characterisation of ternary FGF–FGFR–heparin complexes in solution, will hopefully help resolve the present uncertainty concerning the exact mechanism of FGFR dimerisation. It is possible that the discrepancy observed between crystallographic models reflects real differences in

Acknowledgements

I would like to thank Tom Blundell and Nicholas Harmer for stimulating discussions and comments on the manuscript. I acknowledge research support by the Wellcome Trust.

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:•of special interest••of outstanding interest

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