Characterization of human frataxin missense variants in cancer tissues. Issue 9 (18th June 2019)

• Record Type: Journal Article
• Authors: Petrosino, Maria; Pasquo, Alessandra; Novak, Leonore; Toto, Angelo; Gianni, Stefano; Mantuano, Elide; Veneziano, Liana; Minicozzi, Velia; Pastore, Annalisa; Puglisi, Rita; Capriotti, Emidio; Chiaraluce, Roberta; Consalvi, Valerio
• Editors: Moult, John; Brenner, Steven E.
• Other Names: Karchin Rachel guestEditor.; Pal Lipika R. specialEditor.
• Is Part Of: Human mutation. Volume 40:Issue 9(2019)
• Page Start: 1400
• Page End: 1413
• Publication Date: 2019-06-18
• Subjects: cancer tissues -- human frataxin -- missense variants -- protein folding -- protein stability -- protein variants -- single amino acid substitution -- somatic mutations; Human chromosome abnormalities -- Periodicals; Mutation (Biology) -- Periodicals; 616.04205
• DOI: 10.1002/humu.23789
• Languages: English
• ISSNs: 1059-7794

Abstract

Abstract: 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. Abstract : Human frataxin (FXN) is an iron binding protein involved in mitochondrial Fe‐S clusters assembly, a process fundamental for the functional activity of mitochondrial proteins. The study of the missense variants, selected from COSMIC database, suggests that the effect of the mutations is localised to the neighbourhoods of the mutated residues without affecting the global protein fold. The variants show a decreased stability and a decreased functional activity. Defective function of frataxin may cause defects in mitochondria, leading to increased tumorigenesis.