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The C-type lectin fold as an evolutionary solution for massive sequence variation

Nature Structural & Molecular Biology volume 12, pages 886–892 (2005)Cite this article

Abstract

Only few instances are known of protein folds that tolerate massive sequence variation for the sake of binding diversity. The most extensively characterized is the immunoglobulin fold. We now add to this the C-type lectin (CLec) fold, as found in the major tropism determinant (Mtd), a retroelement-encoded receptor-binding protein of Bordetella bacteriophage. Variation in Mtd, with its ∼1013 possible sequences, enables phage adaptation to Bordetella spp. Mtd is an intertwined, pyramid-shaped trimer, with variable residues organized by its CLec fold into discrete receptor-binding sites. The CLec fold provides a highly static scaffold for combinatorial display of variable residues, probably reflecting a different evolutionary solution for balancing diversity against stability from that in the immunoglobulin fold. Mtd variants are biased toward the receptor pertactin, and there is evidence that the CLec fold is used broadly for sequence variation by related retroelements.

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Figure 1: Mtd variation and structure.
Figure 2: Variable region
Figure 3: Receptor-binding site.
Figure 4: Pertactin association.
Figure 5: Structure-based sequence alignment of Mtd with potentially variable proteins of related retroelements.

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Acknowledgements

This work was supported by a W.M. Keck Distinguished Young Scholars in Medicine Award to P.G., a University of California Discovery Grant to J.F.M. and US National Institutes of Health grants T32GM008326 and F31AI061840 to J.L.M. and F32AI49695 to J.A.L. Discussions with F. Stevens on antibody stability are appreciated, as is help with ITC from S. Bergqvist.

Author information

Author notes

  1. Stephen A McMahon

    Present address: Centre for Biomolecular Sciences, University of St. Andrews, Fife, KY16 9ST, UK

  2. Jeffrey A Lawton

    Present address: Department of Chemistry, Eastern University, 1300 Eagle Road, St. Davids, Pennsylvania, 19087, USA

  3. Donald E Kerkow

    Present address: Scripps Research Institute, 10550 N. Torrey Pines, Mail Stop MB33, La Jolla, California, 92037, USA

  4. Sergei Doulatov

    Present address: Department of Microbiology and Medical Genetics, University of Toronto, Toronto, Ontario, M5G 2C1, Canada

  5. Stephen A McMahon and Jason L Miller: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Chemistry & Biochemistry, University of California at San Diego, La Jolla, 92093, California, USA

    Stephen A McMahon, Jason L Miller, Jeffrey A Lawton & Partho Ghosh

  2. Section of Molecular Biology, University of California at San Diego, La Jolla, 92093, California, USA

    Donald E Kerkow & Partho Ghosh

  3. Department of Microbiology, Immunology and Molecular Genetics, David Geffen School of Medicine and the Molecular Biology Institute, University of California at Los Angeles, Los Angeles, 90095, California, USA

    Asher Hodes, Sergei Doulatov & Jeff F Miller

  4. Departments of Biopharmaceutical Sciences and Pharmaceutical Chemistry, Mission Bay Genentech Hall, University of California at San Francisco, San Francisco, 94143, California, USA

    Marc A Marti-Renom, Eswar Narayanan & Andrej Sali

  5. Centre for Biomolecular Sciences, University of St. Andrews, Fife, KY16 9ST, UK

    Jeffrey A Lawton, Donald E Kerkow & Sergei Doulatov

  6. Department of Chemistry, Eastern University, 1300 Eagle Road, St. Davids, Pennsylvania, 19087, USA

    Stephen A McMahon, Donald E Kerkow & Sergei Doulatov

  7. Scripps Research Institute, 10550 N. Torrey Pines, Mail Stop MB33, La Jolla, California, 92037, USA

    Stephen A McMahon, Jeffrey A Lawton & Sergei Doulatov

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Supplementary information

Supplementary Fig. 1

Topology diagram of Mtd. (PDF 172 kb)

Supplementary Fig. 2

Mtd-P1 and Prn-E associate in a 3:1 complex (PDF 114 kb)

Supplementary Table 1

Data collection, phasing and refinement statistics for MAD (SeMet) structures (PDF 51 kb)

Supplementary Table 2

Data collection and refinement statistics (molecular replacement) (PDF 47 kb)

Supplementary Data (PDF 49 kb)

Supplementary Methods (PDF 145 kb)

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McMahon, S., Miller, J., Lawton, J. et al. The C-type lectin fold as an evolutionary solution for massive sequence variation. Nat Struct Mol Biol 12, 886–892 (2005). https://doi.org/10.1038/nsmb992

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