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Structural basis of S-adenosylmethionine-dependent allosteric transition from active to inactive states in methylenetetrahydrofolate reductase

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  • Kazuhiro Yamada

    (University of Michigan
    University of Michigan
    University of Michigan)

  • Johnny Mendoza

    (University of Michigan)

  • Markos Koutmos

    (University of Michigan
    University of Michigan)

Abstract

Methylenetetrahydrofolate reductase (MTHFR) is a pivotal flavoprotein connecting the folate and methionine methyl cycles, catalyzing the conversion of methylenetetrahydrofolate to methyltetrahydrofolate. Human MTHFR (hMTHFR) undergoes elaborate allosteric regulation involving protein phosphorylation and S-adenosylmethionine (AdoMet)-dependent inhibition, though other factors such as subunit orientation and FAD status remain understudied due to the lack of a functional structural model. Here, we report crystal structures of Chaetomium thermophilum MTHFR (cMTHFR) in both active (R) and inhibited (T) states. We reveal FAD occlusion by Tyr361 in the T-state, which prevents substrate interaction. Remarkably, the inhibited form of cMTHFR accommodates two AdoMet molecules per subunit. In addition, we conducted a detailed investigation of the phosphorylation sites in hMTHFR, three of which were previously unidentified. Based on the structural framework provided by our cMTHFR model, we propose a possible mechanism to explain the allosteric structural transition of MTHFR, including the impact of phosphorylation on AdoMet-dependent inhibition.

Suggested Citation

  • Kazuhiro Yamada & Johnny Mendoza & Markos Koutmos, 2024. "Structural basis of S-adenosylmethionine-dependent allosteric transition from active to inactive states in methylenetetrahydrofolate reductase," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-49327-5
    DOI: 10.1038/s41467-024-49327-5
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    References listed on IDEAS

    as
    1. Bostjan Kobe & Bruce E. Kemp, 1999. "Active site-directed protein regulation," Nature, Nature, vol. 402(6760), pages 373-376, November.
    2. D. Sean Froese & Jolanta Kopec & Elzbieta Rembeza & Gustavo Arruda Bezerra & Anselm Erich Oberholzer & Terttu Suormala & Seraina Lutz & Rod Chalk & Oktawia Borkowska & Matthias R. Baumgartner & Wyatt , 2018. "Structural basis for the regulation of human 5,10-methylenetetrahydrofolate reductase by phosphorylation and S-adenosylmethionine inhibition," Nature Communications, Nature, vol. 9(1), pages 1-13, December.
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