A Unique Mode of Coenzyme A Binding to the Nucleotide Binding Pocket of Human Metastasis Suppressor NME1
Coenzyme A (CoA) is a key cellular metabolite which participates in diverse metabolic pathways, regulation of gene expression and the antioxidant defense mechanism. Human NME1 (hNME1), which is a moonlighting protein, was identified as a major CoA-binding protein. Biochemical studies showed that hNM...
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| Idioma: | inglês |
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2023
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| Acesso em linha: | https://hdl.handle.net/20.500.12008/54159 |
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| _version_ | 1868890133113077760 |
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| author | Tossounian, Maria-Armineh |
| author2 | Hristov, Stefan Denchev Semelak, Jonathan Alexis Yu, Bess Yi Kun Baczynska, Maria Zhao, Yuhan Estrin, Darío Ariel Trujillo, Madia Filonenko, Valeriy Gouge, Jerome Gout, Iván |
| author2_role | author author author author author author author author author author |
| author_browse | Baczynska, Maria Estrin, Darío Ariel Filonenko, Valeriy Gouge, Jerome Gout, Iván Hristov, Stefan Denchev Semelak, Jonathan Alexis Tossounian, Maria-Armineh Trujillo, Madia Yu, Bess Yi Kun Zhao, Yuhan |
| author_facet | Tossounian, Maria-Armineh Hristov, Stefan Denchev Semelak, Jonathan Alexis Yu, Bess Yi Kun Baczynska, Maria Zhao, Yuhan Estrin, Darío Ariel Trujillo, Madia Filonenko, Valeriy Gouge, Jerome Gout, Iván |
| author_role | author |
| collection | COLIBRI |
| dc.contributor.none.fl_str_mv | Tossounian Maria-Armineh, University College London (Reino Unido). Department of Structural and Molecular Biology Hristov Stefan Denchev, University College London (Reino Unido). Department of Structural and Molecular Biology Semelak Jonathan Alexis, Consejo Nacional de Investigaciones Científicas y Técnicas (Argentina). Instituto de Química Física de los Materiales, Medioambiente y Energía Yu Bess Yi Kun, University College London (Reino Unido). Department of Structural and Molecular Biology Baczynska Maria, University College London (Reino Unido). Department of Structural and Molecular Biology Zhao Yuhan, University College London (Reino Unido). Department of Structural and Molecular Biology Estrin Darío Ariel, Consejo Nacional de Investigaciones Científicas y Técnicas (Argentina). Instituto de Química Física de los Materiales, Medioambiente y Energía Trujillo Madia, Universidad de la República (Uruguay). Facultad de Medicina. Departamento de Bioquímica Filonenko Valeriy, National Academy of Sciences of Ukraine (Ucrania). Institute of Molecular Biology and Genetics Gouge Jerome, University of London (Reino Unido). Birkbeck College, Institute of Structural and Molecular Biology Gout Iván, National Academy of Sciences of Ukraine (Ucrania). Institute of Molecular Biology and Genetics |
| dc.creator.none.fl_str_mv | Tossounian, Maria-Armineh Hristov, Stefan Denchev Semelak, Jonathan Alexis Yu, Bess Yi Kun Baczynska, Maria Zhao, Yuhan Estrin, Darío Ariel Trujillo, Madia Filonenko, Valeriy Gouge, Jerome Gout, Iván |
| dc.date.none.fl_str_mv | 2023 2026-03-26T16:22:00Z 2026-03-26T16:22:00Z |
| dc.format.none.fl_str_mv | 17 p. application/pdf |
| dc.identifier.none.fl_str_mv | Tossounian M, Hristov S, Semelak J y otros. A Unique Mode of Coenzyme A Binding to the Nucleotide Binding Pocket of Human Metastasis Suppressor NME1. International Journal of Molecular Sciences [en línea]. 2023;24(11) 17 p. https://hdl.handle.net/20.500.12008/54159 10.3390/ijms24119359 1422-0067 |
| dc.language.none.fl_str_mv | en eng |
| dc.publisher.none.fl_str_mv | MDPI |
| dc.relation.none.fl_str_mv | International Journal of Molecular Sciences. 2023;24(11) |
| dc.rights.none.fl_str_mv | info:eu-repo/semantics/openAccess Licencia Creative Commons Atribución (CC - By 4.0) |
| dc.source.none.fl_str_mv | reponame:COLIBRI instname:Universidad de la República instacron:Universidad de la República |
| dc.subject.none.fl_str_mv | CoAlation NDPK-A structure NM23-H1 NME1 X-ray crystallography Coenzyme A Metastasis suppressor Molecular dynamics Nucleotide binding Protein-metabolite regulation ADENINA ARGININA SITIOS DE UNIÓN COENZIMA A CRISTALOGRAFÍA POR RAYOS X HUMANOS NUCLEÓSIDO DIFOSFATO QUINASAS NM23 GENÉTICA NUCLEÓTIDOS TREONINA |
| dc.title.none.fl_str_mv | A Unique Mode of Coenzyme A Binding to the Nucleotide Binding Pocket of Human Metastasis Suppressor NME1 |
| dc.type.none.fl_str_mv | Artículo info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion |
| description | Coenzyme A (CoA) is a key cellular metabolite which participates in diverse metabolic pathways, regulation of gene expression and the antioxidant defense mechanism. Human NME1 (hNME1), which is a moonlighting protein, was identified as a major CoA-binding protein. Biochemical studies showed that hNME1 is regulated by CoA through both covalent and non-covalent binding, which leads to a decrease in the hNME1 nucleoside diphosphate kinase (NDPK) activity. In this study, we expanded the knowledge on previous findings by focusing on the non-covalent mode of CoA binding to the hNME1. With X-ray crystallography, we solved the CoA bound structure of hNME1 (hNME1-CoA) and determined the stabilization interactions CoA forms within the nucleotide-binding site of hNME1. A hydrophobic patch stabilizing the CoA adenine ring, while salt bridges and hydrogen bonds stabilizing the phosphate groups of CoA were observed. With molecular dynamics studies, we extended our structural analysis by characterizing the hNME1-CoA structure and elucidating possible orientations of the pantetheine tail, which is absent in the X-ray structure due to its flexibility. Crystallographic studies suggested the involvement of arginine 58 and threonine 94 in mediating specific interactions with CoA. Site-directed mutagenesis and CoA-based affinity purifications showed that arginine 58 mutation to glutamate (R58E) and threonine 94 mutation to aspartate (T94D) prevent hNME1 from binding to CoA. Overall, our results reveal a unique mode by which hNME1 binds CoA, which differs significantly from that of ADP binding: the α- and β-phosphates of CoA are oriented away from the nucleotide-binding site, while 3'-phosphate faces catalytic histidine 118 (H118). The interactions formed by the CoA adenine ring and phosphate groups contribute to the specific mode of CoA binding to hNME1. |
| eu_rights_str_mv | openAccess |
| format | article |
| id | anni_90702eea8d03a2666e30833ea53f70bc |
| identifier_str_mv | Tossounian M, Hristov S, Semelak J y otros. A Unique Mode of Coenzyme A Binding to the Nucleotide Binding Pocket of Human Metastasis Suppressor NME1. International Journal of Molecular Sciences [en línea]. 2023;24(11) 17 p. 10.3390/ijms24119359 1422-0067 |
| instacron_str | Universidad de la República |
| institution | Universidad de la República |
| instname_str | Universidad de la República |
| language | eng |
| language_invalid_str_mv | en |
| network_acronym_str | anni |
| network_name_str | oai-lr-anni |
| oai_identifier_str | oai:colibri.udelar.edu.uy:20.500.12008/54159 |
| publishDate | 2023 |
| publishDateSort | 2023 |
| publisher.none.fl_str_mv | MDPI |
| reponame_str | COLIBRI |
| repository.mail.fl_str_mv | |
| repository.name.fl_str_mv | |
| repository_id_str | |
| rights_invalid_str_mv | Licencia Creative Commons Atribución (CC - By 4.0) |
| spelling | A Unique Mode of Coenzyme A Binding to the Nucleotide Binding Pocket of Human Metastasis Suppressor NME1Tossounian, Maria-ArminehHristov, Stefan DenchevSemelak, Jonathan AlexisYu, Bess Yi KunBaczynska, MariaZhao, YuhanEstrin, Darío ArielTrujillo, MadiaFilonenko, ValeriyGouge, JeromeGout, IvánCoAlationNDPK-A structureNM23-H1NME1X-ray crystallographyCoenzyme AMetastasis suppressorMolecular dynamicsNucleotide bindingProtein-metabolite regulationADENINAARGININASITIOS DE UNIÓNCOENZIMA ACRISTALOGRAFÍA POR RAYOS XHUMANOSNUCLEÓSIDO DIFOSFATO QUINASAS NM23GENÉTICANUCLEÓTIDOSTREONINACoenzyme A (CoA) is a key cellular metabolite which participates in diverse metabolic pathways, regulation of gene expression and the antioxidant defense mechanism. Human NME1 (hNME1), which is a moonlighting protein, was identified as a major CoA-binding protein. Biochemical studies showed that hNME1 is regulated by CoA through both covalent and non-covalent binding, which leads to a decrease in the hNME1 nucleoside diphosphate kinase (NDPK) activity. In this study, we expanded the knowledge on previous findings by focusing on the non-covalent mode of CoA binding to the hNME1. With X-ray crystallography, we solved the CoA bound structure of hNME1 (hNME1-CoA) and determined the stabilization interactions CoA forms within the nucleotide-binding site of hNME1. A hydrophobic patch stabilizing the CoA adenine ring, while salt bridges and hydrogen bonds stabilizing the phosphate groups of CoA were observed. With molecular dynamics studies, we extended our structural analysis by characterizing the hNME1-CoA structure and elucidating possible orientations of the pantetheine tail, which is absent in the X-ray structure due to its flexibility. Crystallographic studies suggested the involvement of arginine 58 and threonine 94 in mediating specific interactions with CoA. Site-directed mutagenesis and CoA-based affinity purifications showed that arginine 58 mutation to glutamate (R58E) and threonine 94 mutation to aspartate (T94D) prevent hNME1 from binding to CoA. Overall, our results reveal a unique mode by which hNME1 binds CoA, which differs significantly from that of ADP binding: the α- and β-phosphates of CoA are oriented away from the nucleotide-binding site, while 3'-phosphate faces catalytic histidine 118 (H118). The interactions formed by the CoA adenine ring and phosphate groups contribute to the specific mode of CoA binding to hNME1.MDPITossounian Maria-Armineh, University College London (Reino Unido). Department of Structural and Molecular BiologyHristov Stefan Denchev, University College London (Reino Unido). Department of Structural and Molecular BiologySemelak Jonathan Alexis, Consejo Nacional de Investigaciones Científicas y Técnicas (Argentina). Instituto de Química Física de los Materiales, Medioambiente y EnergíaYu Bess Yi Kun, University College London (Reino Unido). Department of Structural and Molecular BiologyBaczynska Maria, University College London (Reino Unido). Department of Structural and Molecular BiologyZhao Yuhan, University College London (Reino Unido). Department of Structural and Molecular BiologyEstrin Darío Ariel, Consejo Nacional de Investigaciones Científicas y Técnicas (Argentina). Instituto de Química Física de los Materiales, Medioambiente y EnergíaTrujillo Madia, Universidad de la República (Uruguay). Facultad de Medicina. Departamento de BioquímicaFilonenko Valeriy, National Academy of Sciences of Ukraine (Ucrania). Institute of Molecular Biology and GeneticsGouge Jerome, University of London (Reino Unido). Birkbeck College, Institute of Structural and Molecular BiologyGout Iván, National Academy of Sciences of Ukraine (Ucrania). Institute of Molecular Biology and Genetics2026-03-26T16:22:00Z2026-03-26T16:22:00Z2023Artículoinfo:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersion17 p.application/pdfTossounian M, Hristov S, Semelak J y otros. A Unique Mode of Coenzyme A Binding to the Nucleotide Binding Pocket of Human Metastasis Suppressor NME1. International Journal of Molecular Sciences [en línea]. 2023;24(11) 17 p.https://hdl.handle.net/20.500.12008/5415910.3390/ijms241193591422-0067reponame:COLIBRIinstname:Universidad de la Repúblicainstacron:Universidad de la RepúblicaenengInternational Journal of Molecular Sciences. 2023;24(11)Las obras depositadas en el Repositorio se rigen por la Ordenanza de los Derechos de la Propiedad Intelectual de la Universidad de la República.(Res. Nº 91 de C.D.C. de 8/III/1994 – D.O. 7/IV/1994) y por la Ordenanza del Repositorio Abierto de la Universidad de la República (Res. Nº 16 de C.D.C. de 07/10/2014)info:eu-repo/semantics/openAccessLicencia Creative Commons Atribución (CC - By 4.0)oai:colibri.udelar.edu.uy:20.500.12008/541592026-04-14T10:28:29Z |
| spellingShingle | A Unique Mode of Coenzyme A Binding to the Nucleotide Binding Pocket of Human Metastasis Suppressor NME1 Tossounian, Maria-Armineh CoAlation NDPK-A structure NM23-H1 NME1 X-ray crystallography Coenzyme A Metastasis suppressor Molecular dynamics Nucleotide binding Protein-metabolite regulation ADENINA ARGININA SITIOS DE UNIÓN COENZIMA A CRISTALOGRAFÍA POR RAYOS X HUMANOS NUCLEÓSIDO DIFOSFATO QUINASAS NM23 GENÉTICA NUCLEÓTIDOS TREONINA |
| status_str | publishedVersion |
| title | A Unique Mode of Coenzyme A Binding to the Nucleotide Binding Pocket of Human Metastasis Suppressor NME1 |
| title_full | A Unique Mode of Coenzyme A Binding to the Nucleotide Binding Pocket of Human Metastasis Suppressor NME1 |
| title_fullStr | A Unique Mode of Coenzyme A Binding to the Nucleotide Binding Pocket of Human Metastasis Suppressor NME1 |
| title_full_unstemmed | A Unique Mode of Coenzyme A Binding to the Nucleotide Binding Pocket of Human Metastasis Suppressor NME1 |
| title_short | A Unique Mode of Coenzyme A Binding to the Nucleotide Binding Pocket of Human Metastasis Suppressor NME1 |
| title_sort | A Unique Mode of Coenzyme A Binding to the Nucleotide Binding Pocket of Human Metastasis Suppressor NME1 |
| topic | CoAlation NDPK-A structure NM23-H1 NME1 X-ray crystallography Coenzyme A Metastasis suppressor Molecular dynamics Nucleotide binding Protein-metabolite regulation ADENINA ARGININA SITIOS DE UNIÓN COENZIMA A CRISTALOGRAFÍA POR RAYOS X HUMANOS NUCLEÓSIDO DIFOSFATO QUINASAS NM23 GENÉTICA NUCLEÓTIDOS TREONINA |
| url | https://hdl.handle.net/20.500.12008/54159 |