Structural basis for the regulation of human 5,10-methylenetetrahydrofolate reductase by phosphorylation and S-adenosylmethionine inhibition
The folate and methionine cycles are crucial for biosynthesis of lipids, nucleotides and proteins, and production of the methyl donor S-adenosylmethionine (SAM). 5,10-methylenetetrahydrofolate reductase (MTHFR) represents a key regulatory connection between these cycles, generating 5-methyltetrahydr...
| Main Authors: | , , , , , , , , , , |
|---|---|
| Format: | Journal article |
| Language: | English |
| Published: |
Nature Publishing Group
2018
|
| _version_ | 1797098646775267328 |
|---|---|
| author | Froese, DS Kopec, JM Rembeza, E Bezerra, GA Oberholzer, AE Suormala, T Lutz, S Chalk, R Borkowska, O Baumgartner, MR Yue, WW |
| author_facet | Froese, DS Kopec, JM Rembeza, E Bezerra, GA Oberholzer, AE Suormala, T Lutz, S Chalk, R Borkowska, O Baumgartner, MR Yue, WW |
| author_sort | Froese, DS |
| collection | OXFORD |
| description | The folate and methionine cycles are crucial for biosynthesis of lipids, nucleotides and proteins, and production of the methyl donor S-adenosylmethionine (SAM). 5,10-methylenetetrahydrofolate reductase (MTHFR) represents a key regulatory connection between these cycles, generating 5-methyltetrahydrofolate for initiation of the methionine cycle, and undergoing allosteric inhibition by its end product SAM. Our 2.5 Å resolution crystal structure of human MTHFR reveals a unique architecture, appending the well-conserved catalytic TIM-barrel to a eukaryote-only SAM-binding domain. The latter domain of novel fold provides the predominant interface for MTHFR homo-dimerization, positioning the N-terminal serine-rich phosphorylation region near the C-terminal SAM-binding domain. This explains how MTHFR phosphorylation, identified on 11 N-terminal residues (16 in total), increases sensitivity to SAM binding and inhibition. Finally, we demonstrate that the 25-amino-acid inter-domain linker enables conformational plasticity and propose it to be a key mediator of SAM regulation. Together, these results provide insight into the molecular regulation of MTHFR. |
| first_indexed | 2024-03-07T05:12:37Z |
| format | Journal article |
| id | oxford-uuid:dc138ca2-8921-4450-a170-ea8f94aaa40f |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T05:12:37Z |
| publishDate | 2018 |
| publisher | Nature Publishing Group |
| record_format | dspace |
| spelling | oxford-uuid:dc138ca2-8921-4450-a170-ea8f94aaa40f2022-03-27T09:15:17ZStructural basis for the regulation of human 5,10-methylenetetrahydrofolate reductase by phosphorylation and S-adenosylmethionine inhibitionJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:dc138ca2-8921-4450-a170-ea8f94aaa40fEnglishSymplectic Elements at OxfordNature Publishing Group2018Froese, DSKopec, JMRembeza, EBezerra, GAOberholzer, AESuormala, TLutz, SChalk, RBorkowska, OBaumgartner, MRYue, WWThe folate and methionine cycles are crucial for biosynthesis of lipids, nucleotides and proteins, and production of the methyl donor S-adenosylmethionine (SAM). 5,10-methylenetetrahydrofolate reductase (MTHFR) represents a key regulatory connection between these cycles, generating 5-methyltetrahydrofolate for initiation of the methionine cycle, and undergoing allosteric inhibition by its end product SAM. Our 2.5 Å resolution crystal structure of human MTHFR reveals a unique architecture, appending the well-conserved catalytic TIM-barrel to a eukaryote-only SAM-binding domain. The latter domain of novel fold provides the predominant interface for MTHFR homo-dimerization, positioning the N-terminal serine-rich phosphorylation region near the C-terminal SAM-binding domain. This explains how MTHFR phosphorylation, identified on 11 N-terminal residues (16 in total), increases sensitivity to SAM binding and inhibition. Finally, we demonstrate that the 25-amino-acid inter-domain linker enables conformational plasticity and propose it to be a key mediator of SAM regulation. Together, these results provide insight into the molecular regulation of MTHFR. |
| spellingShingle | Froese, DS Kopec, JM Rembeza, E Bezerra, GA Oberholzer, AE Suormala, T Lutz, S Chalk, R Borkowska, O Baumgartner, MR Yue, WW Structural basis for the regulation of human 5,10-methylenetetrahydrofolate reductase by phosphorylation and S-adenosylmethionine inhibition |
| title | Structural basis for the regulation of human 5,10-methylenetetrahydrofolate reductase by phosphorylation and S-adenosylmethionine inhibition |
| title_full | Structural basis for the regulation of human 5,10-methylenetetrahydrofolate reductase by phosphorylation and S-adenosylmethionine inhibition |
| title_fullStr | Structural basis for the regulation of human 5,10-methylenetetrahydrofolate reductase by phosphorylation and S-adenosylmethionine inhibition |
| title_full_unstemmed | Structural basis for the regulation of human 5,10-methylenetetrahydrofolate reductase by phosphorylation and S-adenosylmethionine inhibition |
| title_short | Structural basis for the regulation of human 5,10-methylenetetrahydrofolate reductase by phosphorylation and S-adenosylmethionine inhibition |
| title_sort | structural basis for the regulation of human 5 10 methylenetetrahydrofolate reductase by phosphorylation and s adenosylmethionine inhibition |
| work_keys_str_mv | AT froeseds structuralbasisfortheregulationofhuman510methylenetetrahydrofolatereductasebyphosphorylationandsadenosylmethionineinhibition AT kopecjm structuralbasisfortheregulationofhuman510methylenetetrahydrofolatereductasebyphosphorylationandsadenosylmethionineinhibition AT rembezae structuralbasisfortheregulationofhuman510methylenetetrahydrofolatereductasebyphosphorylationandsadenosylmethionineinhibition AT bezerraga structuralbasisfortheregulationofhuman510methylenetetrahydrofolatereductasebyphosphorylationandsadenosylmethionineinhibition AT oberholzerae structuralbasisfortheregulationofhuman510methylenetetrahydrofolatereductasebyphosphorylationandsadenosylmethionineinhibition AT suormalat structuralbasisfortheregulationofhuman510methylenetetrahydrofolatereductasebyphosphorylationandsadenosylmethionineinhibition AT lutzs structuralbasisfortheregulationofhuman510methylenetetrahydrofolatereductasebyphosphorylationandsadenosylmethionineinhibition AT chalkr structuralbasisfortheregulationofhuman510methylenetetrahydrofolatereductasebyphosphorylationandsadenosylmethionineinhibition AT borkowskao structuralbasisfortheregulationofhuman510methylenetetrahydrofolatereductasebyphosphorylationandsadenosylmethionineinhibition AT baumgartnermr structuralbasisfortheregulationofhuman510methylenetetrahydrofolatereductasebyphosphorylationandsadenosylmethionineinhibition AT yueww structuralbasisfortheregulationofhuman510methylenetetrahydrofolatereductasebyphosphorylationandsadenosylmethionineinhibition |