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bioRxiv · 10.64898/2026.06.19.733337

A comprehensive analysis of calreticulin mutants reveals distinct biophysicochemical proprieties with a potential for refined targeted therapies

Kurt, O. N.·Civelek, E.·Ozturk, B.·Chachoua, I.
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Abstract

Calreticulin mutations in myeloproliferative neoplasms result in the replacement of the C-terminus acidic sequence with a positively charged tail that causes pathological activation of the thrombopoietin. The two canonical variants are Type-1 and Type-2. The remaining are mainly classified as Type-1 or Type-2 like based on the wild type sequence retained. Here, we performed in silico biophysicochemical analyses of 76 CALR exon 9 frameshift variants by their sequence and predicted biophysical properties, complemented by structural modeling of the mutant homodimers. Beyond confirming the Type-1 versus Type-2 distinction, we found that the Type 1-like variants form a continuum of charge architecture along which two reproducible subgroups can be identified, rather than sharply separated classes. This work refines the conventional mechanism-based classification into a charge-resolved framework and provides testable hypotheses linking novel-tail chemistry to receptor activation in CALR-mutant neoplasms and paves the way for improved targeted therapies based on individual mutants characteristics

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Kurt, O. N., Civelek, E., Ozturk, B., Chachoua, I.. 2026-06-24. A comprehensive analysis of calreticulin mutants reveals distinct biophysicochemical proprieties with a potential for refined targeted therapies. https://doi.org/10.64898/2026.06.19.733337

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