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Lookup NU author(s): Linnea Blomgren, Dr Sabrina MackinnonORCiD, Dr Arnaud Basle, Professor Wyatt YueORCiD, Dr Thomas McCorvieORCiD
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© The Author(s) 2024. 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. Here we determine the 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.
Author(s): Blomgren LKM, Huber M, Mackinnon SR, Burer C, Basle A, Yue WW, Froese DS, McCorvie TJ
Publication type: Article
Publication status: Published
Journal: Nature Communications
Year: 2024
Volume: 15
Online publication date: 15/04/2024
Acceptance date: 22/03/2024
Date deposited: 12/09/2024
ISSN (electronic): 2041-1723
Publisher: Springer Nature
URL: https://doi.org/10.1038/s41467-024-47174-y
DOI: 10.1038/s41467-024-47174-y
Data Access Statement: Structures and EM maps have been deposited in the Protein Data Bank (PDB) and Electron Microscopy Data Resource (EMD) under the accession codes of PDB-8QA4/EMDB-18298 (MTHFR + SAH symmetric dis-inhibited state), PDB-8QA5/EMDB-18299 (MTHFR + SAH asymmetric dis-inhibited state) and PDB-8QA6/EMDB-18300 (MTHFR + SAM, inhibited state). Cryo-EM data have been deposited to the Electron Microscopy Public Image Archive (EMPIAR), EMPIAR-11959 (MTHFR + SAH) and EMPIAR-11926 (MTHFR + SAM). Structure not generated in this study, PDB-6FCX, PDB-1ZRQ and PDB-2FMN. All main data supporting the findings of this study are available within the article and Supplementary Information. Source data are provided with this paper.
PubMed id: 38622112
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