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

Abstract

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+.

• Authors: Sara La Manna, Daniele Florio, Concetta Di Natale, Fabiana Napolitano, Anna Maria Malfitano, Paolo A Netti, Ilaria De Benedictis, Daniela Marasco
• Journal: Bioorganic chemistry (Bioorg Chem) Vol. 113 Pg. 104997 (08 2021) ISSN: 1090-2120 [Electronic] United States
• PMID: 34044346 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 Elsevier Inc. All rights reserved.

Chemical References

• NPM1 protein, human
• Nuclear Proteins
• Protein Aggregates
• Nucleophosmin

Topics

• Humans
• Leukemia, Myeloid, Acute (genetics, metabolism)
• Mutation
• Nuclear Proteins (analysis, genetics, metabolism)
• Nucleophosmin
• Protein Aggregates
• Protein Conformation
• Tumor Cells, Cultured