Regulation of metastasis suppressor NME1 by a key metabolic cofactor coenzyme A
The metastasis suppressor protein NME1 is an evolutionarily conserved and multifunctional enzyme that plays an important role in suppressing the invasion and metastasis of tumour cells. The nucleoside diphosphate kinase (NDPK) activity of NME1 is well recognized in balancing the intracellular pools...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2021-08-01
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| Series: | Redox Biology |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2213231721001269 |
| _version_ | 1818435972895866880 |
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| author | Bess Yi Kun Yu Maria-Armineh Tossounian Stefan Denchev Hristov Ryan Lawrence Pallavi Arora Yugo Tsuchiya Sew Yeu Peak-Chew Valeriy Filonenko Sally Oxenford Richard Angell Jerome Gouge Mark Skehel Ivan Gout |
| author_facet | Bess Yi Kun Yu Maria-Armineh Tossounian Stefan Denchev Hristov Ryan Lawrence Pallavi Arora Yugo Tsuchiya Sew Yeu Peak-Chew Valeriy Filonenko Sally Oxenford Richard Angell Jerome Gouge Mark Skehel Ivan Gout |
| author_sort | Bess Yi Kun Yu |
| collection | DOAJ |
| description | The metastasis suppressor protein NME1 is an evolutionarily conserved and multifunctional enzyme that plays an important role in suppressing the invasion and metastasis of tumour cells. The nucleoside diphosphate kinase (NDPK) activity of NME1 is well recognized in balancing the intracellular pools of nucleotide diphosphates and triphosphates to regulate cytoskeletal rearrangement and cell motility, endocytosis, intracellular trafficking, and metastasis. In addition, NME1 was found to function as a protein-histidine kinase, 3′-5′ exonuclease and geranyl/farnesyl pyrophosphate kinase. These diverse cellular functions are regulated at the level of expression, post-translational modifications, and regulatory interactions. The NDPK activity of NME1 has been shown to be inhibited in vitro and in vivo under oxidative stress, and the inhibitory effect mediated via redox-sensitive cysteine residues. In this study, affinity purification followed by mass spectrometric analysis revealed NME1 to be a major coenzyme A (CoA) binding protein in cultured cells and rat tissues. NME1 is also found covalently modified by CoA (CoAlation) at Cys109 in the CoAlome analysis of HEK293/Pank1β cells treated with the disulfide-stress inducer, diamide. Further analysis showed that recombinant NME1 is efficiently CoAlated in vitro and in cellular response to oxidising agents and metabolic stress. In vitro CoAlation of recombinant wild type NME1, but not the C109A mutant, results in the inhibition of its NDPK activity. Moreover, CoA also functions as a competitive inhibitor of the NME1 NDPK activity by binding non-covalently to the nucleotide binding site. Taken together, our data reveal metastasis suppressor protein NME1 as a novel binding partner of the key metabolic regulator CoA, which inhibits its nucleoside diphosphate kinase activity via non-covalent and covalent interactions. |
| first_indexed | 2024-12-14T17:01:23Z |
| format | Article |
| id | doaj.art-1a888cb0c73e41febf4761fac8db29c6 |
| institution | Directory Open Access Journal |
| issn | 2213-2317 |
| language | English |
| last_indexed | 2024-12-14T17:01:23Z |
| publishDate | 2021-08-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Redox Biology |
| spelling | doaj.art-1a888cb0c73e41febf4761fac8db29c62022-12-21T22:53:50ZengElsevierRedox Biology2213-23172021-08-0144101978Regulation of metastasis suppressor NME1 by a key metabolic cofactor coenzyme ABess Yi Kun Yu0Maria-Armineh Tossounian1Stefan Denchev Hristov2Ryan Lawrence3Pallavi Arora4Yugo Tsuchiya5Sew Yeu Peak-Chew6Valeriy Filonenko7Sally Oxenford8Richard Angell9Jerome Gouge10Mark Skehel11Ivan Gout12Department of Structural and Molecular Biology, University College London, London, WC1E 6BT, United KingdomDepartment of Structural and Molecular Biology, University College London, London, WC1E 6BT, United KingdomDepartment of Structural and Molecular Biology, University College London, London, WC1E 6BT, United KingdomDepartment of Structural and Molecular Biology, University College London, London, WC1E 6BT, United KingdomDepartment of Structural and Molecular Biology, University College London, London, WC1E 6BT, United KingdomDepartment of Structural and Molecular Biology, University College London, London, WC1E 6BT, United KingdomMRC Laboratory of Molecular Biology, Cambridge Biomedical Campus, Cambridge, CB2 0QH, United KingdomDepartment of Cell Signaling, Institute of Molecular Biology and Genetics, Kyiv, 143, UkraineSchool of Pharmacy, University College London, London, WC1N 1AX, United KingdomSchool of Pharmacy, University College London, London, WC1N 1AX, United KingdomInstitute of Structural and Molecular Biology, Birkbeck College, London, WC1E 7HX, United KingdomMRC Laboratory of Molecular Biology, Cambridge Biomedical Campus, Cambridge, CB2 0QH, United KingdomDepartment of Structural and Molecular Biology, University College London, London, WC1E 6BT, United Kingdom; Department of Cell Signaling, Institute of Molecular Biology and Genetics, Kyiv, 143, Ukraine; Corresponding author. Department of Structural and Molecular Biology, University College London, London, WC1E 6BT, United Kingdom.The metastasis suppressor protein NME1 is an evolutionarily conserved and multifunctional enzyme that plays an important role in suppressing the invasion and metastasis of tumour cells. The nucleoside diphosphate kinase (NDPK) activity of NME1 is well recognized in balancing the intracellular pools of nucleotide diphosphates and triphosphates to regulate cytoskeletal rearrangement and cell motility, endocytosis, intracellular trafficking, and metastasis. In addition, NME1 was found to function as a protein-histidine kinase, 3′-5′ exonuclease and geranyl/farnesyl pyrophosphate kinase. These diverse cellular functions are regulated at the level of expression, post-translational modifications, and regulatory interactions. The NDPK activity of NME1 has been shown to be inhibited in vitro and in vivo under oxidative stress, and the inhibitory effect mediated via redox-sensitive cysteine residues. In this study, affinity purification followed by mass spectrometric analysis revealed NME1 to be a major coenzyme A (CoA) binding protein in cultured cells and rat tissues. NME1 is also found covalently modified by CoA (CoAlation) at Cys109 in the CoAlome analysis of HEK293/Pank1β cells treated with the disulfide-stress inducer, diamide. Further analysis showed that recombinant NME1 is efficiently CoAlated in vitro and in cellular response to oxidising agents and metabolic stress. In vitro CoAlation of recombinant wild type NME1, but not the C109A mutant, results in the inhibition of its NDPK activity. Moreover, CoA also functions as a competitive inhibitor of the NME1 NDPK activity by binding non-covalently to the nucleotide binding site. Taken together, our data reveal metastasis suppressor protein NME1 as a novel binding partner of the key metabolic regulator CoA, which inhibits its nucleoside diphosphate kinase activity via non-covalent and covalent interactions.http://www.sciencedirect.com/science/article/pii/S2213231721001269NDPKCoenzyme AProtein CoAlationOxidative stressMetastasis suppressorRedox regulation |
| spellingShingle | Bess Yi Kun Yu Maria-Armineh Tossounian Stefan Denchev Hristov Ryan Lawrence Pallavi Arora Yugo Tsuchiya Sew Yeu Peak-Chew Valeriy Filonenko Sally Oxenford Richard Angell Jerome Gouge Mark Skehel Ivan Gout Regulation of metastasis suppressor NME1 by a key metabolic cofactor coenzyme A Redox Biology NDPK Coenzyme A Protein CoAlation Oxidative stress Metastasis suppressor Redox regulation |
| title | Regulation of metastasis suppressor NME1 by a key metabolic cofactor coenzyme A |
| title_full | Regulation of metastasis suppressor NME1 by a key metabolic cofactor coenzyme A |
| title_fullStr | Regulation of metastasis suppressor NME1 by a key metabolic cofactor coenzyme A |
| title_full_unstemmed | Regulation of metastasis suppressor NME1 by a key metabolic cofactor coenzyme A |
| title_short | Regulation of metastasis suppressor NME1 by a key metabolic cofactor coenzyme A |
| title_sort | regulation of metastasis suppressor nme1 by a key metabolic cofactor coenzyme a |
| topic | NDPK Coenzyme A Protein CoAlation Oxidative stress Metastasis suppressor Redox regulation |
| url | http://www.sciencedirect.com/science/article/pii/S2213231721001269 |
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