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 remains unstudied because no external agonist has been discovered. Here, we describe the structure and function of a marine sponge-derived MPL agonist, thrombocorticin (ThC). ThC-induced activation persists due to limited receptor internalization. Strong synergy between ThC and thrombopoietin suggests that ThC catalyzes the formation of receptor dimers on the cell surface. We show that MPL is subject to sugar-mediated activation and that lectin-mediated activation kinetics differ from cytokine-mediated activation kinetics. Our data demonstrated the potential of lectins to provide deeper insight into human pathogenesis.
One-sentence summary A marine sponge lectin catalyzes thrombopoietin receptor dimerization and activation, exhibiting strong synergy with thrombopoietin, and modulates the internalization of the receptor.
Competing Interest Statement
The authors have declared no competing interest.