Updated project metadata. Calreticulin (CALR) is a master lectin chaperone that guides the proper folding of integral membrane proteins in the endoplasmic reticulum. In healthy cells, CALR transiently and non-specifically interacts with thousands of immature N-glycosylated proteins through its N-terminal glycan-binding domain. Conversely, frameshift mutants of CALR turn into rogue cytokine by acquiring the ability to stably and specifically interact with the Thrombopoietin Receptor (TpoR). Strikingly, this interaction induces activation of TpoR leading to myeloproliferative neoplasms, blood cancers resulting from the overproduction of blood cells. Using a multidisciplinary approach, we unveil how the CALR frameshift mutations result in structural overhaul of the entire protein and identify the structural basis of its acquired specificty for TpoR. We further describe the mechanisms by zhich complex formation triggers TpoR dimerization and activation. In addition, we provide the first complete dynamic conformational footprints of both wild-type and mutant CALR and identify novel potentially targetable sites.