Hidden pathway for cytokine receptor activation: Structural insights into a marine sponge-derived lectin that activates the thrombopoietin receptor via recognition of the fucose moiety

Authors:
  • HWHiromi Watari
    Hiromi Watari
  • HKHiromu Kageyama
    Hiromu Kageyama
  • NMNami Masubuchi
    Nami Masubuchi
  • HNHiroya Nakajima
    Hiroya Nakajima
  • KOKako Onodera
    Kako Onodera
  • PFPamela J. Focia
    Pamela J. Focia
  • TOTakumi Oshiro
    Takumi Oshiro
  • TMTakashi Matsui
    Takashi Matsui
  • YKYoshio Kodera
    Yoshio Kodera
  • TOTomohisa Ogawa
    Tomohisa Ogawa
  • TYTakeshi Yokoyama
    Takeshi Yokoyama
  • MHMakoto Hirayama
    Makoto Hirayama
Preprint
Publisher website
Google Scholar
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 constitutively activates the receptor. However, the molecular basis for this mechanism has not been studied because no external agonists existed. We describe the structure and function of a marine sponge-derived MPL agonist, thrombocorticin (ThC), a homodimerized lectin with calcium-dependent fucose-binding properties. ThC-induced 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. MPL is subject to sugar-mediated activation, where the kinetics differ from those of cytokines. This result suggests the presence of diverse receptor activation pathways in human thrombopoiesis. One-sentence summary: A marine sponge lectin catalyzes thrombopoietin receptor dimerization and activation, exhibiting strong synergy with thrombopoietin, and modulates internalization of the receptor.

This publication has 27 references indexed in Scilit: