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Structural basis for the regulation of human 5,10-methylenetetrahydrofolate reductase by phosphorylation and S-adenosylmethionine inhibition
- Source :
- Froese, D Sean; Kopec, Jolanta; Rembeza, Elzbieta; Bezerra, Gustavo Arruda; Oberholzer, Anselm Erich; Suormala, Terttu; Lutz, Seraina; Chalk, Rod; Borkowska, Oktawia; Baumgartner, Matthias R; Yue, Wyatt W (2018). Structural basis for the regulation of human 5,10-methylenetetrahydrofolate reductase by phosphorylation and S-adenosylmethionine inhibition. Nature Communications, 9:2261.
- Publication Year :
- 2018
-
Abstract
- 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.
Details
- Database :
- OAIster
- Journal :
- Froese, D Sean; Kopec, Jolanta; Rembeza, Elzbieta; Bezerra, Gustavo Arruda; Oberholzer, Anselm Erich; Suormala, Terttu; Lutz, Seraina; Chalk, Rod; Borkowska, Oktawia; Baumgartner, Matthias R; Yue, Wyatt W (2018). Structural basis for the regulation of human 5,10-methylenetetrahydrofolate reductase by phosphorylation and S-adenosylmethionine inhibition. Nature Communications, 9:2261.
- Notes :
- application/pdf, info:doi/10.5167/uzh-160676, English
- Publication Type :
- Electronic Resource
- Accession number :
- edsoai.on1416170773
- Document Type :
- Electronic Resource