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Crystal structure of the NK1 fragment of HGF/SF suggests a novel mode for growth factor dimerization and receptor binding

Nature Structural Biology volume 6, pages 72–79 (1999)Cite this article

Abstract

Although ligand-induced receptor dimerization is a common prerequisite for receptor activation, the mode by which different growth factors bind their receptors and cause them to dimerize varies considerably. Here we report the crystal structure at 2.5 Å resolution of NK1, a receptor-binding fragment and a natural splice variant of hepatocyte growth factor/scatter factor (HGF/SF). NK1 assembles as a homodimer in the asymmetric unit, revealing a novel mode of growth factor dimerization produced by close packing of the N domain of one subunit and the kringle domain of the other, thus bringing the two linkers in close proximity. The structure suggests the presence of a binding site for heparan sulfate chains and a mechanism by which the NK1 dimer may engage two receptor molecules through clusters of amino acids located on each protomer and on opposite surfaces of the homodimer. We also report that short (14-mer) heparin fragments effectively dimerize NK1 in solution, implying that heparan sulfate chains may stabilize the NK1 dimer. These results provide a basis for the agonistic activity of NK1 and have implications for the mechanism of receptor binding of HGF/SF.

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Figure 1: Schematic representation of the domain structure of HGF/SF.
Figure 2: a, Ribbon representation of the NK1 homodimer observed in the crystal's asymmetric unit.
Figure 3: a, Three-dimensional superposition of the N domain of HGF/SF resolved by NMR (gray) and the N domain of protomer B resolved by X-ray crystallography (green).
Figure 4: a, Space-filling representation of the NK1 protomer.
Figure 5: a, Ribbon representation of the NK1 homodimer (the view is from the opposite side of that in Fig. 2a).
Figure 6: Solution behavior of NK1 in the absence or presence of 14-mer heparin fragments.

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Acknowledgements

We thank S. Batley for assistance with the NK1 constructs and D. Lietha, H. de Jonge and B. Mulloy (National Institute for Biological Standards and Controls) for contributions to the early analysis of NK1–heparin interactions. Work in E.G.'s laboratory was supported by the MRC and the European Union's Biomed Programme. Work in T.L.B.'s laboratory was supported by the Imperial Cancer Research Fund and Wellcome Trust. Work in R.A.B.'s laboratory was supported by the National Cancer Institute, Department of Health and Human Services (DHHS) under contract with ABL. E.G. also has a part time teaching appointment at the Institute C Golgi of the University of Pavia, Italy.

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Authors and Affiliations

  1. Department of Biochemistry, University of Cambridge, 80 Tennis Court Road, Cambridge, CB2 1GA, UK

    Dimitri Y. Chirgadze & Tom L. Blundell

  2. Growth Factors Group, MRC Centre, Hills Road, Cambridge, CB2 2QH, UK

    Jonathan P. Hepple & Ermanno Gherardi

  3. Macromolecular NMR Section, ABL-Basic Research Program, NCI-Frederick Cancer Research and Development Center, Fredrick, 21702-1201, Maryland, USA

    Hongjun Zhou & R. Andrew Byrd

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  1. Dimitri Y. Chirgadze
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Correspondence to Ermanno Gherardi.

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Chirgadze, D., Hepple, J., Zhou, H. et al. Crystal structure of the NK1 fragment of HGF/SF suggests a novel mode for growth factor dimerization and receptor binding. Nat Struct Mol Biol 6, 72–79 (1999). https://doi.org/10.1038/4947

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