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Cited by 3Folate and B Vitamins ResearchEnzyme Structure and FunctionPorphyrin Metabolism and Disorders

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Structural insights into cobalamin loading and reactivation of human methionine synthase

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Ferreira, Douglas S. M., McLennan, Katie, Diamond, Calum, Vollmar, Melanie, Kiyani, Wasim, Froese, D. Sean, Kopec, Jola, Bailey, Henry J., Chalk, Rod, Baslé, Arnaud, Elkins, Jonathan M., Coker, Jesse A., Yue, Wyatt W., McCorvie, Thomas J.·2026·Nature Communications
DOI 10.1038/s41467-026-72899-3PMC PMC13376404

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Abstract

Human methionine synthase (MTR) is an essential enzyme of one carbon metabolism. Consisting of a catalytic N-half and a cobalamin binding C-half, MTR utilises this intricate organometallic cofactor in the methyl transfer from methyltetrahydrofolate to homocysteine producing methionine. Cobalamin loading into MTR, and its subsequent activation, requires methylmalonic aciduria and homocystinuria Type D (MMADHC) protein and methionine synthase reductase (MTRR), respectively. However, the molecular basis of cobalamin binding and activation of human MTR aided by MMADHC and MTRR remains unknown. Here, using cryo-electron microscopy, we determine structures of human MTR in its apo, and cobalamin bound states. Apo MTR adopts a conformation where the two halves of the enzyme act independently with the C-half posed to bind cobalamin. Binding of cobalamin and its activation causes conformational changes in MTR that result in a flexible catalytically active state. AlphaFold predictions, validated by interaction studies, show that MMADHC interacts with the C-half of apo MTR to facilitate cobalamin loading. Unexpectedly we found that MTRR interacts at two distinct sites within the C-half of MTR which may aid in activation. Collectively these findings lay the groundwork to uncover the mechanisms through how MMADHC and MTRR coordinate cobalamin loading and activation of human MTR.

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Metadata

Authors
Ferreira, D. S. M., McLennan, K., Diamond, C., Vollmar, M., Kiyani, W., Froese, D. S., Kopec, J., Bailey, H. J., Chalk, R., Baslé, A., Elkins, J. M., Coker, J. A., Yue, W. W., & McCorvie, T. J.
Affiliations
  • University of Oxford (GB)
  • Newcastle University (GB)
  • European Bioinformatics Institute (GB)
  • University of Zurich (CH)
  • Goethe University Frankfurt (DE)
  • Cleveland Clinic (US)
Corresponding author
  • Yue, Wyatt W.
  • McCorvie, Thomas J.
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2026-05-11
Volume
17
Issue
1
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/s41467-026-72899-3
PMC
PMC13376404
OpenAlex
W4416091531
Cited by
3
References
2
Citations by year
2026: 3
FWCI
15.52
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Funders
  • Wellcome Trust (206161/Z/17/Z, 092809/Z/10/Z, 218785/Z/19/Z)
  • RCUK | 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 › Structural Biology › Enzyme Structure and Function
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Porphyrin Metabolism and Disorders
Keywords
methionine synthase, MTRR, one-carbon metabolism, conformational change, methyltetrahydrofolate, homocysteine, methyltransferase, enzyme structure
MeSH terms
Enzyme Activation, Ferredoxin-NADP Reductase, Humans, Models, Molecular, Protein Binding, Protein Conformation, 5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase, Vitamin B 12, Cryoelectron Microscopy, Intracellular Signaling Peptides and Proteins

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