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Through combined molecular dynamics simulation, clustered regularly interspaced short palindromic repeats (CRISPR) and calcium imaging studies on the wild type and mutated isoforms of calreticulin, the mechanism underlying the calreticulin INDEL induced ET was investigated at the molecular level. Our results demonstrate that mutations in exon\u20109 could lead to significant conformational variations of calreticulin structure and thereby reducing its interaction with calcium ions due to decreased electrostatic contributions. The consequence of mutations on calreticulin's structural integrity was revealed by identifying the key residues and their roles in calcium binding. Furthermore, mutations implemented by CRISPR\u2010Cas9 in exon\u20109 showed diminished calcium signaling in HEK\u2010293T cells, which agree well with our <jats:italic>in\u2010silico<\/jats:italic> findings. The current study might help in understanding the variations of molecular interactions between calreticulin's exon\u20109 and calcium ions during physiological and pathological conditions. The results might also provide useful information for designing novel therapeutic approaches targeting ET.<\/jats:p>","DOI":"10.1002\/cbin.12015","type":"journal-article","created":{"date-parts":[[2023,3,19]],"date-time":"2023-03-19T14:28:55Z","timestamp":1679236135000},"page":"1229-1246","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Unraveling the connection between calreticulin and myeloproliferative neoplasms via calcium signaling"],"prefix":"10.1002","volume":"47","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4778-5955","authenticated-orcid":false,"given":"Amit","family":"Jaiswal","sequence":"first","affiliation":[{"name":"Institute of Aging Research Hangzhou Normal University  Hangzhou Zhejiang China"},{"name":"Faculty of Biological Sciences Friedrich Schiller University Jena 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