NME6 is a phosphotransfer-inactive, monomeric NME/NDPK family member and functions in complexes at the interface of mitochondrial inner membrane and matrix
| Autor: | Lucija Ačkar, Martina Radić, Maja Herak Bosnar, Malgorzata Tokarska-Schlattner, Helena Ćetković, Vlatka Godinić Mikulčić, Frédéric Lamarche, Stéphane Attia, Nikolina Škrobot Vidaček, Cécile Cottet, Bastien Lucien Jean Proust, Uwe Schlattner |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Mitochondrial translation
QH301-705.5 QD415-436 Mitochondrion nm23 Biochemistry General Biochemistry Genetics and Molecular Biology 03 medical and health sciences 0302 clinical medicine NDP kinase NME Mitochondria RCC1L WBSCR16 Inner membrane Biology (General) Inner mitochondrial membrane Biology 030304 developmental biology Mitochondrial ribosome assembly 0303 health sciences Chemistry Research Histidine kinase Basic Medical Sciences Nucleoside-diphosphate kinase Cell biology 030220 oncology & carcinogenesis Signal transduction TP248.13-248.65 Biotechnology |
| Zdroj: | Cell and Bioscience Cell & Bioscience, Vol 11, Iss 1, Pp 1-23 (2021) Cell & Bioscience |
| Popis: | Background NME6 is a member of the nucleoside diphosphate kinase (NDPK/NME/Nm23) family which has key roles in nucleotide homeostasis, signal transduction, membrane remodeling and metastasis suppression. The well-studied NME1-NME4 proteins are hexameric and catalyze, via a phospho-histidine intermediate, the transfer of the terminal phosphate from (d)NTPs to (d)NDPs (NDP kinase) or proteins (protein histidine kinase). For the NME6, a gene/protein that emerged early in eukaryotic evolution, only scarce and partially inconsistent data are available. Here we aim to clarify and extend our knowledge on the human NME6. Results We show that NME6 is mostly expressed as a 186 amino acid protein, but that a second albeit much less abundant isoform exists. The recombinant NME6 remains monomeric, and does not assemble into homo-oligomers or hetero-oligomers with NME1-NME4. Consequently, NME6 is unable to catalyze phosphotransfer: it does not generate the phospho-histidine intermediate, and no NDPK activity can be detected. In cells, we could resolve and extend existing contradictory reports by localizing NME6 within mitochondria, largely associated with the mitochondrial inner membrane and matrix space. Overexpressing NME6 reduces ADP-stimulated mitochondrial respiration and complex III abundance, thus linking NME6 to dysfunctional oxidative phosphorylation. However, it did not alter mitochondrial membrane potential, mass, or network characteristics. Our screen for NME6 protein partners revealed its association with NME4 and OPA1, but a direct interaction was observed only with RCC1L, a protein involved in mitochondrial ribosome assembly and mitochondrial translation, and identified as essential for oxidative phosphorylation. Conclusions NME6, RCC1L and mitoribosomes localize together at the inner membrane/matrix space where NME6, in concert with RCC1L, may be involved in regulation of the mitochondrial translation of essential oxidative phosphorylation subunits. Our findings suggest new functions for NME6, independent of the classical phosphotransfer activity associated with NME proteins. |
| Databáze: | OpenAIRE |
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