Structural analysis for glycolipid recognition by the C-type lectins Mincle and MCL

Atsushi Furukawa, Jun Kamishikiryo, Daiki Mori, Kenji Toyonaga, Yuki Okabe, Aya Toji, Ryo Kanda, Yasunobu Miyake, Toyoyuki Ose, Sho Yamasaki, Katsumi Maenaka

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    Abstract

    Mincle [macrophage inducible Ca2+-dependent (C-type) lectin; CLEC4E] and MCL (macrophage C-type lectin; CLEC4D) are receptors for the cord factor TDM (trehalose-6,6′-dimycolate), a unique glycolipid of mycobacterial cell-surface components, and activate immune cells to confer adjuvant activity. Although it is known that receptor-TDM interactions require both sugar and lipid moieties of TDM, the mechanisms of glycolipid recognition by Mincle and MCL remain unclear. We here report the crystal structures of Mincle, MCL, and the Mincle-citric acid complex. The structures revealed that these receptors are capable of interacting with sugar in a Ca 2+-dependent manner, as observed in other C-type lectins. However, Mincle and MCL uniquely possess shallow hydrophobic regions found adjacent to their putative sugar binding sites, which reasonably locate for recognition of fatty acid moieties of glycolipids. Functional studies using mutant receptors as well as glycolipid ligands support this deduced binding mode. These results give insight into the molecular mechanism of glycolipid recognition through C-type lectin receptors, which may provide clues to rational design for effective adjuvants.

    Original languageEnglish
    Pages (from-to)17438-17443
    Number of pages6
    JournalProceedings of the National Academy of Sciences of the United States of America
    Volume110
    Issue number43
    DOIs
    Publication statusPublished - Oct 22 2013

    All Science Journal Classification (ASJC) codes

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    Furukawa, A., Kamishikiryo, J., Mori, D., Toyonaga, K., Okabe, Y., Toji, A., Kanda, R., Miyake, Y., Ose, T., Yamasaki, S., & Maenaka, K. (2013). Structural analysis for glycolipid recognition by the C-type lectins Mincle and MCL. Proceedings of the National Academy of Sciences of the United States of America, 110(43), 17438-17443. https://doi.org/10.1073/pnas.1312649110