A marine sponge-derived lectin reveals hidden pathway for thrombopoietin receptor activation

Hiromi Watari, Hiromu Kageyama, Nami Masubuchi, Hiroya Nakajima, Kako Onodera, Pamela J. Focia, Takumi Oshiro, Takashi Matsui, Yoshio Kodera, Tomohisa Ogawa, Takeshi Yokoyama, Makoto Hirayama, Kanji Hori, Douglas M. Freymann, Misa Imai, Norio Komatsu, Marito Araki*, Yoshikazu Tanaka*, Ryuichi Sakai*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

N-glycan-mediated activation of the thrombopoietin receptor (MPL) under pathological conditions has been implicated in myeloproliferative neoplasms induced by mutant calreticulin, which forms an endogenous receptor-agonist complex that traffics to the cell surface and constitutively activates the receptor. However, the molecular basis for this mechanism is elusive because oncogenic activation occurs only in the cell-intrinsic complex and is thus cannot be replicated with external agonists. Here, we describe the structure and function of a marine sponge-derived MPL agonist, thrombocorticin (ThC), a homodimerized lectin with calcium-dependent fucose-binding properties. In-depth characterization of lectin-induced activation showed that, similar to oncogenic activation, sugar chain-mediated activation persists due to limited receptor internalization. The strong synergy between ThC and thrombopoietin suggests that ThC catalyzes the formation of receptor dimers on the cell surface. Overall, the existence of sugar-mediated MPL activation, in which the mode of activation is different from the original ligand, suggests that receptor activation is unpredictably diverse in living organisms.

Original languageEnglish (US)
Article number7262
JournalNature communications
Volume13
Issue number1
DOIs
StatePublished - Dec 2022

ASJC Scopus subject areas

  • General Physics and Astronomy
  • General Chemistry
  • General Biochemistry, Genetics and Molecular Biology

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  • Thrombocorticin in complex with Ca2+ and mannose

    Watari, H. (Contributor), Kageyama, H. (Contributor), Masubuchi, N. (Contributor), Nakajima, H. (Contributor), Onodera, K. (Contributor), Focia, P. J. (Contributor), Oshiro, T. (Contributor), Matsui, T. (Contributor), Kodera, Y. (Contributor), Ogawa, T. (Contributor), Yokoyama, T. (Contributor), Hirayama, M. (Contributor), Hori, K. (Contributor), Freymann, D. M. (Contributor), Imai, M. (Contributor), Komatsu, N. (Contributor), Araki, M. (Contributor), Tanaka, Y. (Contributor) & Sakai, R. (Contributor), Protein Data Bank (PDB), Jul 13 2022

    Dataset

  • SeMet derivative of Thrombocorticin

    Watari, H. (Contributor), Kageyama, H. (Contributor), Masubuchi, N. (Contributor), Nakajima, H. (Contributor), Onodera, K. (Contributor), Focia, P. J. (Contributor), Oshiro, T. (Contributor), Matsui, T. (Contributor), Kodera, Y. (Contributor), Ogawa, T. (Contributor), Yokoyama, T. (Contributor), Hirayama, M. (Contributor), Hori, K. (Contributor), Freymann, D. M. (Contributor), Imai, M. (Contributor), Komatsu, N. (Contributor), Araki, M. (Contributor), Tanaka, Y. (Contributor) & Sakai, R. (Contributor), Protein Data Bank (PDB), Jul 6 2022

    Dataset

  • Thrombocorticin

    Watari, H. (Contributor), Kageyama, H. (Contributor), Masubuchi, N. (Contributor), Nakajima, H. (Contributor), Onodera, K. (Contributor), Focia, P. J. (Contributor), Oshiro, T. (Contributor), Matsui, T. (Contributor), Kodera, Y. (Contributor), Ogawa, T. (Contributor), Yokoyama, T. (Contributor), Hirayama, M. (Contributor), Hori, K. (Contributor), Freymann, D. M. (Contributor), Imai, M. (Contributor), Komatsu, N. (Contributor), Araki, M. (Contributor), Tanaka, Y. (Contributor) & Sakai, R. (Contributor), Protein Data Bank (PDB), Jul 6 2022

    Dataset

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