Department of Pharmacy, University of Naples "Federico II", 80134 Naples, Italy.
Interdisciplinary Research Centre on Biomaterials (CRIB), Department of Ingegneria Chimica dei Materiali e della Produzione Industriale (DICMAPI), University of Naples "Federico II", 8012 Naples, Italy.
Bioorg Chem. 2021 Aug;113:104997. doi: 10.1016/j.bioorg.2021.104997. Epub 2021 May 18.
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+.
通常，蛋白质的相互作用是细胞用来调节生长和适应不同应激条件（包括突变）的生理过程。在急性髓系白血病（AML）的一个亚型中，核仁磷酸蛋白 1（NPM1）蛋白的突变导致其异常的细胞质定位错误（NPMc+）。我们最近指出，包括 NPMc+中最常见突变所在 C 末端结构域（CTD）在内的蛋白质区域具有淀粉样倾向：它们能够在体外形成具有纤维状形态的纤维状细胞毒性聚集物。在此，我们分析了包括 NPMc+中罕见 AML 突变在内的几种肽的构象特征。通过不同的光谱学、显微镜和细胞检测，我们评估了氨基酸组成在确定淀粉样倾向方面的重要性，特别是在罕见的 AML 突变中。这项研究可以为细胞质 NPM1c+中的突变的结构后果增加一些知识。
