Structural basis for the regulation of human 5,10-methylenetetrahydrofolate reductase by phosphorylation and S-adenosylmethionine inhibition

D. Sean Froese (), Jolanta Kopec, Elzbieta Rembeza, Gustavo Arruda Bezerra, Anselm Erich Oberholzer, Terttu Suormala, Seraina Lutz, Rod Chalk, Oktawia Borkowska, Matthias R. Baumgartner and Wyatt W. Yue ()
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D. Sean Froese: University Children’s Hospital
Jolanta Kopec: University of Oxford
Elzbieta Rembeza: University of Oxford
Gustavo Arruda Bezerra: University of Oxford
Anselm Erich Oberholzer: Structural Biology Community Laenggasse (sbcl)
Terttu Suormala: University Children’s Hospital
Seraina Lutz: University Children’s Hospital
Rod Chalk: University of Oxford
Oktawia Borkowska: University of Oxford
Matthias R. Baumgartner: University Children’s Hospital
Wyatt W. Yue: University of Oxford

Nature Communications, 2018, vol. 9, issue 1, 1-13

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-04735-2

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