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bioRxiv · 10.1101/271593

Structural basis of human 5,10-methylenetetrahydrofolate reductase (MTHFR) regulation by phosphorylation and S-adenosylmethionine inhibition

Froese, D. S.·Kopec, J.·Rembeza, E.·Bezerra, G. A.·Oberholzer, A.·Suormala, T.·Lutz, S.·Chalk, R.·Borkowska, O.·Baumgartner, M.·Yue, W.
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Abstract

The folate and methionine cycles are crucial to the biosynthesis of lipids, nucleotides and proteins, and production of the global 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 [A] 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 into proximity with the C-terminal SAM-binding domain. This explains how MTHFR phosphorylation, identified on 11 N-terminal residues (16-total), increases sensitivity to SAM binding and inhibition. Finally, we demonstrate the 25-amino-acid inter-domain linker enables conformational plasticity and propose it to be a key mediator of SAM regulation.

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Froese, D. S., Kopec, J., Rembeza, E., Bezerra, G. A., Oberholzer, A., Suormala, T., Lutz, S., Chalk, R., Borkowska, O., Baumgartner, M., Yue, W.. 2018-02-26. Structural basis of human 5,10-methylenetetrahydrofolate reductase (MTHFR) regulation by phosphorylation and S-adenosylmethionine inhibition. https://doi.org/10.1101/271593

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