Conservation of the C-type lectin fold for massive sequence variation in a Treponema diversity-generating retroelement.

Johanne Le Coq, Partho Ghosh

Department of Chemistry and Biochemistry, University of California at San Diego, La Jolla, CA 92093, USA.

Proceedings of the National Academy of Sciences of the United States of America 2011 Aug 30

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Anticipatory ligand binding through massive protein sequence variation is rare in biological systems, having been observed only in the vertebrate adaptive immune response and in a phage diversity-generating retroelement (DGR). Earlier work has demonstrated that the prototypical DGR variable protein, major tropism determinant (Mtd), meets the demands of anticipatory ligand binding by novel means through the C-type lectin (CLec) fold. However, because of the low sequence identity among DGR variable proteins, it has remained unclear whether the CLec fold is a general solution for DGRs. We have addressed this problem by determining the structure of a second DGR variable protein, TvpA, from the pathogenic oral spirochete Treponema denticola. Despite its weak sequence identity to Mtd (∼16%), TvpA was found to also have a CLec fold, with predicted variable residues exposed in a ligand-binding site. However, this site in TvpA was markedly more variable than the one in Mtd, reflecting the unprecedented approximate 10(20) potential variability of TvpA. In addition, similarity between TvpA and Mtd with formylglycine-generating enzymes was detected. These results provide strong evidence for the conservation of the formylglycine-generating enzyme-type CLec fold among DGRs as a means of accommodating massive sequence variation.

Citation

Johanne Le Coq, Partho Ghosh. Conservation of the C-type lectin fold for massive sequence variation in a Treponema diversity-generating retroelement. Proceedings of the National Academy of Sciences of the United States of America. 2011 Aug 30;108(35):14649-53