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Structural basis for the shielding function of the dynamic trypanosome variant surface glycoprotein coat

Nature Microbiology volume 2, pages 1523–1532 (2017)Cite this article

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Abstract

The most prominent defence of the unicellular parasite Trypanosoma brucei against the host immune system is a dense coat that comprises a variant surface glycoprotein (VSG). Despite the importance of the VSG family, no complete structure of a VSG has been reported. Making use of high-resolution structures of individual VSG domains, we employed small-angle X-ray scattering to elucidate the first two complete VSG structures. The resulting models imply that the linker regions confer great flexibility between domains, which suggests that VSGs can adopt two main conformations to respond to obstacles and changes of protein density, while maintaining a protective barrier at all times. Single-molecule diffusion measurements of VSG in supported lipid bilayers substantiate this possibility, as two freely diffusing populations could be detected. This translates into a highly flexible overall topology of the surface VSG coat, which displays both lateral movement in the plane of the membrane and variation in the overall thickness of the coat.

The parasite Trypanosoma brucei thrives in the bloodstream and tissue spaces of its mammalian host, where it is prone to attack by the immune system. As a first defence against the immune response, the bloodstream form of trypanosomes is coated with a dense layer of variant surface glycoprotein (VSG). This layer constitutes at least 95% of the cell-surface proteins1,2 and impairs the identification of epitopes of invariant surface proteins by the immune system3,4,5,6. Only a single VSG gene is transcribed at any given time from a specific genomic locus, the VSG expression site (ES). However, the VSG itself is highly immunogenic and, once detected by the immune system, antibodies specific for the expressed VSG isoform will facilitate a rapid clearance of the infection7,8. To establish a persistent infection, the parasite employs antigenic variation to switch the expression to an antigenically distinct VSG from a library that encodes several hundred VSGs9. This continual switching forces the host immune system constantly to chase novel antigen types. The shielding function that VSG is thought to provide has been described only anecdotally and, owing to a lack of a complete VSG structural model, the mechanism remains unclear.

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Fig. 1: Crystal structure of the NTD of VSG M1.1.
Fig. 2: Solution structure of the CTD of VSG M1.1.
Fig. 3: Rigid-body models of two complete VSGs.
Fig. 4: Flexibility of linker L1 in VSG M1.1.
Fig. 5: Diffusion behaviour of mfVSG M1.1 incorporated into a solid supported lipid bilayer.
Fig. 6: VSG packing on the cell surface.

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Acknowledgements

This work was supported by the Deutsche Forschungsgemeinschaft (DFG, grants EN 305, GRK 1114 to M.E. and SFB 630 to M.E. and C.K.), and the Wellcome Trust (grant 022758/Z/03/Z to M.Ca.). A.-S.S. and M.Cv. were funded from grant ERC StG 2013-337283 of the European Research Council and supported by the DFG GRK 1962. M.E. is a member of the Wilhelm Conrad Röntgen-Center for Complex Material Systems. We thank the Helmholtz-Zentrum Berlin for the allocation of synchrotron radiation beamtime and the staff of the BESSY at beamline 14.1 for technical assistance. The SAXS experiments were performed on beamline BM29 at ESRF. We are grateful to A. Round at the ESRF for providing assistance in using beamline BM29 and for invaluable tips concerning data analysis. We thank D. Nietlispach for the acquisition of NMR data and B. Morriswood for critical reading of the manuscript.

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  1. Martha Brennich

    Present address: European Molecular Biology Laboratory, 71 Avenue des Martyrs, BP 181, 38042, Grenoble, France

  2. Thomas Bartossek and Nicola G. Jones contributed equally to this work.

Authors and Affiliations

  1. Department of Cell and Developmental Biology, Theodor-Boveri-Institute, Biocenter, University of Würzburg, 97074, Würzburg, Germany

    Thomas Bartossek, Nicola G. Jones, Marius Glogger, Susanne Fenz & Markus Engstler

  2. Rudolf Virchow Center for Experimental Biomedicine, Institute for Structural Biology, University of Würzburg, 97080, Würzburg, Germany

    Christin Schäfer, Jochen Kuper & Caroline Kisker

  3. PULS Group, Institut für Theoretische Physik and the Excellence Cluster: Engineering of Advanced Materials, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91052, Erlangen, Germany

    Mislav Cvitković & Ana-Sunčana Smith

  4. Group for Computational Life Sciences, Division of Physical Chemistry, Ruđer Bošković Institute, 10000, Zagreb, Croatia

    Mislav Cvitković & Ana-Sunčana Smith

  5. Department of Biochemistry, University of Cambridge, Cambridge, CB2 1GA, UK

    Helen R. Mott & Mark Carrington

  6. European Synchrotron Radiation Facility, 71 Avenue des Martyrs, CS 40220, 38042, Grenoble, France

    Martha Brennich

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Contributions

T.B., N.G.J. and M.E. conceived the study, T.B., N.G.J., M.Ca., A.-A.S., S.F., C.K. and M.E. designed the research; T.B., N.G.J., M.G. and S.F. performed the experiments; T.B., N.G.J., C.S., M.Cv., M.G., H.R.M., J.K., M.B., A.-S.S., S.F. and M.E. analysed the data; T.B., N.G.J. and M.E. wrote the paper with contributions from M.Cv., A.-S.S. and S.F. during manuscript editing.

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Correspondence to Nicola G. Jones or Markus Engstler.

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Bartossek, T., Jones, N.G., Schäfer, C. et al. Structural basis for the shielding function of the dynamic trypanosome variant surface glycoprotein coat. Nat Microbiol 2, 1523–1532 (2017). https://doi.org/10.1038/s41564-017-0013-6

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