Dynamic inter-domain transformations mediate the allosteric regulation of human 5, 10-methylenetetrahydrofolate reductase.
In: Nature communications, Jg. 15 (2024-04-15), Heft 1, S. 3248
Online
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Zugriff:
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.
(© 2024. The Author(s).)
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Dynamic inter-domain transformations mediate the allosteric regulation of human 5, 10-methylenetetrahydrofolate reductase.
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Autor/in / Beteiligte Person: | Blomgren, LKM ; Huber, M ; Mackinnon, SR ; Bürer, C ; Baslé, A ; Yue, WW ; Froese, DS ; McCorvie, TJ |
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Zeitschrift: | Nature communications, Jg. 15 (2024-04-15), Heft 1, S. 3248 |
Veröffentlichung: | [London] : Nature Pub. Group, 2024 |
Medientyp: | academicJournal |
ISSN: | 2041-1723 (electronic) |
DOI: | 10.1038/s41467-024-47174-y |
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