NME6 is a phosphotransfer-inactive, monomeric NME/NDPK family member and functions in complexes at the interface of mitochondrial inner membrane and matrix

Abstract 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...

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Autores principales:	Bastien Proust, Martina Radić, Nikolina Škrobot Vidaček, Cécile Cottet, Stéphane Attia, Frédéric Lamarche, Lucija Ačkar, Vlatka Godinić Mikulčić, Malgorzata Tokarska-Schlattner, Helena Ćetković, Uwe Schlattner, Maja Herak Bosnar
Formato:	article
Lenguaje:	EN
Publicado:	BMC 2021
Materias:	NDP kinase NME nm23 Mitochondria RCC1L WBSCR16 Biotechnology TP248.13-248.65 Biology (General) QH301-705.5 Biochemistry QD415-436
Acceso en línea:	https://doaj.org/article/6a3e0a4c508a420bb6a3fed81f79b808
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spelling	oai:doaj.org-article:6a3e0a4c508a420bb6a3fed81f79b8082021-11-21T12:31:44ZNME6 is a phosphotransfer-inactive, monomeric NME/NDPK family member and functions in complexes at the interface of mitochondrial inner membrane and matrix10.1186/s13578-021-00707-02045-3701https://doaj.org/article/6a3e0a4c508a420bb6a3fed81f79b8082021-11-01T00:00:00Zhttps://doi.org/10.1186/s13578-021-00707-0https://doaj.org/toc/2045-3701Abstract 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.Bastien ProustMartina RadićNikolina Škrobot VidačekCécile CottetStéphane AttiaFrédéric LamarcheLucija AčkarVlatka Godinić MikulčićMalgorzata Tokarska-SchlattnerHelena ĆetkovićUwe SchlattnerMaja Herak BosnarBMCarticleNDP kinaseNMEnm23MitochondriaRCC1LWBSCR16BiotechnologyTP248.13-248.65Biology (General)QH301-705.5BiochemistryQD415-436ENCell & Bioscience, Vol 11, Iss 1, Pp 1-23 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	NDP kinase NME nm23 Mitochondria RCC1L WBSCR16 Biotechnology TP248.13-248.65 Biology (General) QH301-705.5 Biochemistry QD415-436
spellingShingle	NDP kinase NME nm23 Mitochondria RCC1L WBSCR16 Biotechnology TP248.13-248.65 Biology (General) QH301-705.5 Biochemistry QD415-436 Bastien Proust Martina Radić Nikolina Škrobot Vidaček Cécile Cottet Stéphane Attia Frédéric Lamarche Lucija Ačkar Vlatka Godinić Mikulčić Malgorzata Tokarska-Schlattner Helena Ćetković Uwe Schlattner Maja Herak Bosnar NME6 is a phosphotransfer-inactive, monomeric NME/NDPK family member and functions in complexes at the interface of mitochondrial inner membrane and matrix
description	Abstract 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.
format	article
author	Bastien Proust Martina Radić Nikolina Škrobot Vidaček Cécile Cottet Stéphane Attia Frédéric Lamarche Lucija Ačkar Vlatka Godinić Mikulčić Malgorzata Tokarska-Schlattner Helena Ćetković Uwe Schlattner Maja Herak Bosnar
author_facet	Bastien Proust Martina Radić Nikolina Škrobot Vidaček Cécile Cottet Stéphane Attia Frédéric Lamarche Lucija Ačkar Vlatka Godinić Mikulčić Malgorzata Tokarska-Schlattner Helena Ćetković Uwe Schlattner Maja Herak Bosnar
author_sort	Bastien Proust
title	NME6 is a phosphotransfer-inactive, monomeric NME/NDPK family member and functions in complexes at the interface of mitochondrial inner membrane and matrix
title_short	NME6 is a phosphotransfer-inactive, monomeric NME/NDPK family member and functions in complexes at the interface of mitochondrial inner membrane and matrix
title_full	NME6 is a phosphotransfer-inactive, monomeric NME/NDPK family member and functions in complexes at the interface of mitochondrial inner membrane and matrix
title_fullStr	NME6 is a phosphotransfer-inactive, monomeric NME/NDPK family member and functions in complexes at the interface of mitochondrial inner membrane and matrix
title_full_unstemmed	NME6 is a phosphotransfer-inactive, monomeric NME/NDPK family member and functions in complexes at the interface of mitochondrial inner membrane and matrix
title_sort	nme6 is a phosphotransfer-inactive, monomeric nme/ndpk family member and functions in complexes at the interface of mitochondrial inner membrane and matrix
publisher	BMC
publishDate	2021
url	https://doaj.org/article/6a3e0a4c508a420bb6a3fed81f79b808
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NME6 is a phosphotransfer-inactive, monomeric NME/NDPK family member and functions in complexes at the interface of mitochondrial inner membrane and matrix

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