Istituto di Cristallografia - CNR

Type F mutation of nucleophosmin 1 Acute Myeloid Leukemia: A tale of disorder and aggregation

Protein aggregation is suggested as a reversible, wide-spread physiological process used by cells to regulate their growth and adapt to different stress conditions. Nucleophosmin 1(NPM1) protein is an abundant multifunctional nucleolar chaperone and its gene is the most frequently mutated in Acute Myeloid Leukemia (AML) patients. So far, the role of NPM1 mutations in leukemogenesis has remained largely elusive considering that they have the double effect of unfolding the C-terminal domain (CTD) and delocalizing the protein in the cytosol (NPM1c+). This mislocalization heavily impacts on cell cycle regulation. Our recent investigations unequivocally demonstrated an amyloid aggregation propensity introduced by AML mutations. Herein, employing complementary biophysical assays, we have characterized a N-terminal extended version of type F AML mutation of CTD and proved that it is able to form assemblies with amyloid character and fibrillar morphology. The present study represents an additional phase of knowledge to deepen the roles exerted by different types of cytoplasmatic NPM1c+ forms to develop in the future potential therapeutics for their selective targeting.

International journal of biological macromolecules
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La Manna S.; Florio D.; Di Natale C.; Scognamiglio P.L.; Sibillano T.; Netti P.A.; Giannini C.; Marasco D.