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

Stephen A McMahon^1, 5, 6, Jason L Miller^1, 6, Jeffrey A Lawton^1, 5, Donald E Kerkow^2, 5, Asher Hodes³, Marc A Marti-Renom⁴, Sergei Doulatov^3, 5, Eswar Narayanan⁴, Andrej Sali⁴, Jeff F Miller³ & Partho Ghosh^1, 2

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

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

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, California 90095, USA.

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

⁵  Present addresses: Centre for Biomolecular Sciences, University of St. Andrews, Fife KY16 9ST, UK (S.A.M.), Department of Chemistry, Eastern University, 1300 Eagle Road, St. Davids, Pennsylvania 19087, USA (J.A.L.), Scripps Research Institute, 10550 N. Torrey Pines, Mail Stop MB33, La Jolla, California 92037, USA (D.E.K.) and Department of Microbiology and Medical Genetics, University of Toronto, Toronto, Ontario M5G 2C1, Canada (S.D.).

⁶  These authors contributed equally to this work.

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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