6FNU

Structure of S. cerevisiae Methylenetetrahydrofolate reductase 1, catalytic domain

Summary for 6FNU

• Entry DOI: 10.2210/pdb6fnu/pdb
• Descriptor: Methylenetetrahydrofolate reductase 1, FLAVIN-ADENINE DINUCLEOTIDE (3 entities in total)
• Functional Keywords: reductase, one carbon metabolism, tim barrel, folate metabolism, structural genomics, structural genomics consortium, sgc, oxidoreductase
• Biological source: Saccharomyces cerevisiae (Baker's yeast)
• Total number of polymer chains: 1
• Total formula weight: 35580.30

Authors

Kopec, J.,Rembeza, E.,Bezerra, G.A.,Newman, J.,Bountra, C.,Froese, D.S.,Baumgartner, M.,Yue, W.W.,Structural Genomics Consortium (SGC) (deposition date: 2018-02-05, release date: 2018-03-07, Last modification date: 2024-05-08)

Primary citation

Froese, D.S.,Kopec, J.,Rembeza, E.,Bezerra, G.A.,Oberholzer, A.E.,Suormala, T.,Lutz, S.,Chalk, R.,Borkowska, O.,Baumgartner, M.R.,Yue, W.W.
Structural basis for the regulation of human 5,10-methylenetetrahydrofolate reductase by phosphorylation and S-adenosylmethionine inhibition.
Nat Commun, 9:2261-2261, 2018

PubMed 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.

PubMed: 29891918
DOI: 10.1038/s41467-018-04735-2

Experimental method

X-RAY DIFFRACTION (1.56 Å)