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Dynamic inter-domain transformations mediate the allosteric regulation of human 5, 10-methylenetetrahydrofolate reductase
Open accessPreprint — published as 10.1038/s41467-024-47174-y
Abstract
5,10-methylenetetrahydrofolate reductase (MTHFR) commits folate-derived one-carbon units to generate the methyl-donor S-adenosyl-L-methionine (SAM). Eukaryotic MTHFR appends to the well-conserved catalytic domain (CD) a unique regulatory domain (RD) that confers feedback inhibition by SAM. We determined cryo-electron microscopy structures of human MTHFR bound to SAM and its demethylated product S-adenosyl-L-homocysteine (SAH). In the active state, with the RD bound to a single SAH, the CD is flexible and exposes its active site for catalysis. However, in the inhibited state the RD pocket is remodelled, exposing a second SAM-binding site that was previously occluded. Dual-SAM bound MTHFR demonstrates a substantially rearranged inter-domain linker that reorients the CD, inserts a loop into the active site, positions Tyr404 to bind the cofactor FAD, and blocks substrate access. Our data therefore explain the long-distance regulatory mechanism of MTHFR inhibition, underpinned by the transition between dual-SAM and single-SAH binding in response to cellular methylation status.
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Metadata
- Authors
- Blomgren, L. K. M., Huber, M., Mackinnon, S. R., Bürer, C., Baslé, A., Yue, W. W., Froese, D. S., & McCorvie, T. J.
- Affiliations
- University of Zurich (CH)
- Newcastle University (GB)
- University of Oxford (GB)
- Corresponding author
- Yue, Wyatt W.
- Froese, D. Sean
- McCorvie, Thomas J.
- ORCID
- Venue
- Nature Communications
- Publisher
- openRxiv
- Published
- 2023-08-02
- Volume
- 15
- Issue
- 1
- Pages
- 3248-3248
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC11018872
- OpenAlex
- W4394802497
- Cited by
- 18
- References
- 1
- Citations by year
- 2026: 8 · 2025: 3 · 2024: 7
- FWCI
- 5.80
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by
- Locations
- Nature Communications (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Newcastle University ePrints (Newcastle Univesity) (cc-by)
- Funders
- National Science Foundation
- Wellcome Trust (206161, Z/17/Z, 206161/Z/17/Z)
- University of Oxford
- Newcastle University
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (206161, 192505, 310030)
- Universität Zürich
- Biotechnology and Biological Sciences Research Council (BB/R013942/1)
- Topics
- Health Sciences › Nursing › Nutrition and Dietetics › Folate and B Vitamins Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Biochemical and Molecular Research
- Keywords
- methylenetetrahydrofolate reductase, allosteric regulation, S-adenosylhomocysteine, S-adenosylmethionine, product inhibition, interdomain linker, protein structural dynamics, folate metabolism, cryo-EM structure
- MeSH terms
- Allosteric Regulation, Humans, Methylation, S-Adenosylmethionine, Cryoelectron Microscopy, Methylenetetrahydrofolate Reductase (NADPH2)
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