The GT to GC single nucleotide polymorphism at the beginning of an alternative exon 2C of human MTH1 gene confers an amino terminal extension that functions as a mitochondrial targeting signal
| Autor: | Daisuke Yoshimura, Yasunari Sakai, Shigenori Iwai, Toshiro Hara, Hisanobu Oda, Yusaku Nakabeppu, Masato Furuichi, Dongchon Kang |
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| Rok vydání: | 2006 |
| Předmět: |
Gene isoform
Mitochondrial DNA Recombinant Fusion Proteins Amino Acid Motifs Molecular Sequence Data Single-nucleotide polymorphism Protein Sorting Signals Mitochondrion Biology Polymorphism Single Nucleotide Cell Line Exon Adenosine Triphosphate Drug Discovery Humans Nucleotide Amino Acid Sequence Gene Genetics (clinical) chemistry.chemical_classification Hydrolysis Exons Molecular biology Fusion protein Phosphoric Monoester Hydrolases Mitochondria Isoenzymes Alternative Splicing Protein Transport DNA Repair Enzymes chemistry Molecular Medicine |
| Zdroj: | Journal of Molecular Medicine. 84:660-670 |
| ISSN: | 1432-1440 0946-2716 |
| Popis: | Human MTH1 protein hydrolyzes oxidized purine nucleotides 8-oxo-2'-deoxyguanosine triphosphate (8-oxo-dGTP), 2-OH-dATP or their ribo-forms to their monophosphates, thus minimizing replicational and transcriptional errors both in the nuclei and mitochondria. MTH1 suppresses mitochondrial dysfunction and cell death caused by H(2)O(2). Furthermore, MTH1 suppresses the transient increase in 8-oxoguanine in mitochondrial DNA in the dopaminergic nerve terminals in mouse striatum after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine administration, and it protects the nerve terminals. We previously reported that a novel MTH1 allele with a single nucleotide polymorphism (SNP) in its exon 2c segment encodes the fourth MTH1 isoform, namely, MTH1a (p26), in addition to the three known isoforms, MTH1b (p22), c (p21), and d (p18). Another SNP located in exon 4 of the MTH1 gene, which is closely linked to the SNP in exon 2c, substitutes the Val83 residue in MTH1d with Met83. We herein show that all MTH1 isoforms efficiently hydrolyzed 2-OH-dATP and 8-oxo-dGTP. The amino terminal region of MTH1a functioned as a mitochondrial targeting signal when it was expressed in the HeLa cells as a fusion protein with enhanced green fluorescent protein. The cellular fractionation revealed that MTH1a(Met83) was localized in the mitochondria to the same extent as was MTH1d(Val83). However, the mitochondrial translocation of MTH1d(Met83) was less efficient than that of MTH1d(Val83). |
| Databáze: | OpenAIRE |
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