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

DOI: 10.1038/s41467-018-04735-2 DOI Help

Authors: D. Sean Froese (University Children’s Hospital, Zurich) , Jolanta Kopec (Structural Genomics Consortium, University of Oxford) , Elzbieta Rembeza (Structural Genomics Consortium, University of Oxford) , Gustavo Arruda Bezerra (Structural Genomic Consortium, University of Oxford) , Anselm Erich Oberholzer (Structural Biology Community Laenggasse (sbcl)) , Terttu Suormala (University Children’s Hospital, Zurich) , Seraina Lutz (University Children’s Hospital, Zurich) , Rod Chalk (Structural Genomic Consortium, University of Oxford) , Oktawia Borkowska (University Children’s Hospital, Zurich) , Matthias R. Baumgartner (University Children’s Hospital, Zurich) , Wyatt W. Yue (Structural Genomics Consortium, University of Oxford)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Nature Communications , VOL 9

State: Published (Approved)
Published: June 2018
Diamond Proposal Number(s): 10619 , 51433

Open Access Open Access

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.

Journal Keywords: Mass spectrometry; Oxidoreductases; SAXS; X-ray crystallography

Subject Areas: Biology and Bio-materials


Instruments: B21-High Throughput SAXS , I04-1-Macromolecular Crystallography (fixed wavelength)

Documents:
s41467-018-04735-2.pdf