1. Structural basis of S-adenosylmethionine-dependent allosteric transition from active to inactive states in methylenetetrahydrofolate reductase.
- Author
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Yamada K, Mendoza J, and Koutmos M
- Subjects
- Allosteric Regulation, Phosphorylation, Humans, Crystallography, X-Ray, Models, Molecular, Flavin-Adenine Dinucleotide metabolism, Flavin-Adenine Dinucleotide chemistry, Methylenetetrahydrofolate Reductase (NADPH2) metabolism, Methylenetetrahydrofolate Reductase (NADPH2) chemistry, Methylenetetrahydrofolate Reductase (NADPH2) genetics, S-Adenosylmethionine metabolism, S-Adenosylmethionine chemistry, Chaetomium enzymology, Chaetomium metabolism, Chaetomium genetics
- 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., (© 2024. The Author(s).)
- Published
- 2024
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