7F9J

Thrombocorticin Q25K in complex with Ca2+

Summary for 7F9J

• Entry DOI: 10.2210/pdb7f9j/pdb
• Related: 7F91 7F9F 7F9G
• Descriptor: Thrombocorticin Q25K mutant, CALCIUM ION (3 entities in total)
• Functional Keywords: bioactive protein, thrombocorticin, sugar binding protein
• Biological source: Corticium sp. (in: Fungi)
• Total number of polymer chains: 2
• Total formula weight: 29726.65

Authors

Kageyama, H.,Onodera, K.,Sakai, R.,Tanaka, Y. (deposition date: 2021-07-04, release date: 2022-07-06, Last modification date: 2024-10-16)

Primary citation

Watari, H.,Kageyama, H.,Masubuchi, N.,Nakajima, H.,Onodera, K.,Focia, P.J.,Oshiro, T.,Matsui, T.,Kodera, Y.,Ogawa, T.,Yokoyama, T.,Hirayama, M.,Hori, K.,Freymann, D.M.,Imai, M.,Komatsu, N.,Araki, M.,Tanaka, Y.,Sakai, R.
A marine sponge-derived lectin reveals hidden pathway for thrombopoietin receptor activation.
Nat Commun, 13:7262-7262, 2022

PubMed 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.

PubMed: 36433967
DOI: 10.1038/s41467-022-34921-2

Experimental method

X-RAY DIFFRACTION (1.1 Å)