6FCX

Structure of human 5,10-methylenetetrahydrofolate reductase (MTHFR)

Summary for 6FCX

• Entry DOI: 10.2210/pdb6fcx/pdb
• Descriptor: Methylenetetrahydrofolate reductase, FLAVIN-ADENINE DINUCLEOTIDE, S-ADENOSYL-L-HOMOCYSTEINE, ... (5 entities in total)
• Functional Keywords: one carbon metabolism, rossmann fold, s-adenosyl-methionine, structural genomics, structural genomics consortium, sgc, oxidoreductase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 143826.15

Authors

Kopec, J.,Bezerra, G.A.,Oberholzer, A.E.,Rembeza, E.,Sorrell, F.J.,Chalk, R.,Borkowska, O.,Ellis, K.,Kupinska, K.,Krojer, T.,Burgess-Brown, N.,Von Delft, F.,Arrowsmith, C.,Edwards, A.,Bountra, C.,Froese, D.S.,Baumgartner, M.,Yue, W.W.,Structural Genomics Consortium (SGC) (deposition date: 2017-12-21, release date: 2018-05-16, Last modification date: 2018-07-04)

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 (2.5 Å)