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The ligand-binding face of the semaphorins revealed by the high-resolution crystal structure of SEMA4D

Nature Structural & Molecular Biology volume 10, pages 843–848 (2003)Cite this article

Abstract

Semaphorins, proteins characterized by an extracellular sema domain, regulate axon guidance, immune function and angiogenesis. The crystal structure of SEMA4D (residues 1–657) shows the sema topology to be a seven-bladed β-propeller, revealing an unexpected homology with integrins. The sema β-propeller contains a distinctive 77-residue insertion between β-strands C and D of blade 5. Blade 7 is followed by a domain common to plexins, semaphorins and integrins (PSI domain), which forms a compact cysteine knot abutting the side of the propeller, and an Ig-like domain. The top face of the β-propeller presents prominent loops characteristic of semaphorins. In addition to limited contact between the Ig-like domains, the homodimer is stabilized through extensive interactions between the top faces in a sector of the β-propeller used for heterodimerization in integrins. This face of the propeller also mediates ligand binding in integrins, and functional data for semaphorin-receptor interactions map to the equivalent surface.

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Figure 1: The crystal structure of sSEMA4D.
Figure 2: Structural and sequence alignments of the semaphorins and integrins.
Figure 3: Functional information mapped to the sSEMA4D structure.

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Acknowledgements

We are grateful to R. Manso-Sancho for advice and assistance in protein expression, L. Lyne and W. Lu for cell culture, A. Chedatol and L. Tamagnone for biological assays of sSEMA4D, T. Batuwangala for additional work on semaphorins, N. Zaccai for data collection, J. Brown, J. Grimes and P. Roche for help with computation and S. Naylor for discussion. We thank M. Walsh and colleagues at BM14 as well as the staff of the ESRF and EMBL outstation in Grenoble. This work was funded by Cancer Research UK with additional support from the European Commission Integrated Program SPINE. D.I.S. and E.Y.J. are supported by the UK Medical Research Council and Cancer Research UK, respectively.

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  1. Nasim Mavaddat

    Present address: Department of Pathology, Cambridge University, Tennis Court Road, Cambridge, CB2 1QP, UK

Authors and Affiliations

  1. Division of Structural Biology, Henry Wellcome Building for Genomic Medicine, University of Oxford, Roosevelt Drive, Oxford, OX3 7BN, UK

    Christopher A Love, Karl Harlos, David I Stuart, E Yvonne Jones & Robert M Esnouf

  2. Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford, OX1 3RE, UK

    Nasim Mavaddat

  3. Nuffield Department of Clinical Medicine, University of Oxford, John Radcliffe Hospital, Oxford, OX3 9DU, UK

    Simon J Davis

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Love, C., Harlos, K., Mavaddat, N. et al. The ligand-binding face of the semaphorins revealed by the high-resolution crystal structure of SEMA4D. Nat Struct Mol Biol 10, 843–848 (2003). https://doi.org/10.1038/nsb977

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