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Oncogenic CALR mutant C-terminus mediates dual binding to the thrombopoietin receptor triggering complex dimerization and activation. | LitMetric

AI Article Synopsis

  • CALR frameshift mutations are a major cause of myeloproliferative neoplasms (MPN), where CALR typically interacts with proteins but mutants interact differently.
  • These mutants bind strongly to the Thrombopoietin Receptor (TpoR), causing it to activate continuously, which is linked to disease progression.
  • The study reveals how the mutant CALR's structure allows it to effectively dimerize with TpoR, suggesting new targets for potential treatments.*

Article Abstract

Calreticulin (CALR) frameshift mutations represent the second cause of myeloproliferative neoplasms (MPN). In healthy cells, CALR transiently and non-specifically interacts with immature N-glycosylated proteins through its N-terminal domain. Conversely, CALR frameshift mutants turn into rogue cytokines by stably and specifically interacting with the Thrombopoietin Receptor (TpoR), inducing its constitutive activation. Here, we identify the basis of the acquired specificity of CALR mutants for TpoR and define the mechanisms by which complex formation triggers TpoR dimerization and activation. Our work reveals that CALR mutant C-terminus unmasks CALR N-terminal domain, rendering it more accessible to bind immature N-glycans on TpoR. We further find that the basic mutant C-terminus is partially α-helical and define how its α-helical segment concomitantly binds acidic patches of TpoR extracellular domain and induces dimerization of both CALR mutant and TpoR. Finally, we propose a model of the tetrameric TpoR-CALR mutant complex and identify potentially targetable sites.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC10076285PMC
http://dx.doi.org/10.1038/s41467-023-37277-3DOI Listing

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