Conformational consequences of NPM1 rare mutations: An aggregation perspective in Acute Myeloid Leukemia

Often proteins association is a physiological process used by cells to regulate their growth and to adapt to different stress conditions, including mutations. In the case of a subtype of Acute Myeloid Leukemia (AML), mutations of nucleophosmin 1 (NPM1) protein cause its aberrant cytoplasmatic mislocalization (NPMc+). We recently pointed out an amyloidogenic propensity of protein regions including the most common mutations of NPMc+ located in the C-terminal domain (CTD): they were able to form, in vitro, amyloid cytotoxic aggregates with fibrillar morphology. Herein, we analyzed the conformational characteristics of several peptides including rare AML mutations of NPMc+. By means of different spectroscopic, microscopic and cellular assays we evaluated the importance of amino acid composition, among rare AML mutations, to determine amyloidogenic propensity. This study could add a piece of knowledge to the structural consequences of mutations in cytoplasmatic NPM1c+.

Automated summary

Protein association is a physiological process used by cells to regulate growth and adapt to stress conditions, including mutations. Mutations in the NPM1 protein can lead to the formation of amyloidogenic aggregates with fibrillar morphology, which could be harmful to cells. Analyzing the conformational characteristics of peptides with rare AML mutations of NPMc+ provides valuable insights into the structural consequences of cytoplasmic NPM1c+ mutations.