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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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.
The authors declare no competing financial interests.
Topology diagram of Mtd. (PDF 172 kb)
Mtd-P1 and Prn-E associate in a 3:1 complex (PDF 114 kb)
Data collection, phasing and refinement statistics for MAD (SeMet) structures (PDF 51 kb)
Data collection and refinement statistics (molecular replacement) (PDF 47 kb)
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