Dipartimento di Scienze Biochimiche "A. Rossi Fanelli", Sapienza University of Rome, Rome, Italy.
IRCCS Istituto Neurologico Carlo Besta, Milano, Italy.
Hum Mutat. 2019 Sep;40(9):1400-1413. doi: 10.1002/humu.23789. Epub 2019 Jun 18.
Human frataxin is an iron-binding protein involved in the mitochondrial iron-sulfur (Fe-S) clusters assembly, a process fundamental for the functional activity of mitochondrial proteins. Decreased level of frataxin expression is associated with the neurodegenerative disease Friedreich ataxia. Defective function of frataxin may cause defects in mitochondria, leading to increased tumorigenesis. Tumor-initiating cells show higher iron uptake, a decrease in iron storage and a reduced Fe-S clusters synthesis and utilization. In this study, we selected, from COSMIC database, the somatic human frataxin missense variants found in cancer tissues p.D104G, p.A107V, p.F109L, p.Y123S, p.S161I, p.W173C, p.S181F, and p.S202F to analyze the effect of the single amino acid substitutions on frataxin structure, function, and stability. The spectral properties, the thermodynamic and the kinetic stability, as well as the molecular dynamics of the frataxin missense variants found in cancer tissues point to local changes confined to the environment of the mutated residues. The global fold of the variants is not altered by the amino acid substitutions; however, some of the variants show a decreased stability and a decreased functional activity in comparison with that of the wild-type protein.
人铁蛋白是一种与线粒体铁硫簇（Fe-S）组装相关的铁结合蛋白，该过程对线粒体蛋白的功能活性至关重要。铁蛋白表达水平降低与神经退行性疾病弗里德里希共济失调有关。铁蛋白功能缺陷可能导致线粒体功能缺陷，从而增加肿瘤发生的风险。肿瘤起始细胞表现出更高的铁摄取、铁储存减少以及 Fe-S 簇合成和利用减少。在这项研究中，我们从 COSMIC 数据库中选择了在癌症组织中发现的人铁蛋白错义变体 p.D104G、p.A107V、p.F109L、p.Y123S、p.S161I、p.W173C、p.S181F 和 p.S202F，以分析单个氨基酸取代对铁蛋白结构、功能和稳定性的影响。癌症组织中发现的铁蛋白错义变体的光谱特性、热力学和动力学稳定性以及分子动力学表明，局部变化仅限于突变残基的环境。变体的全局折叠并未因氨基酸取代而改变；然而，与野生型蛋白相比，一些变体显示出稳定性降低和功能活性降低。
