Structural insights into cobalamin loading and reactivation of human methionine synthase
Year: 2026
Type: article
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.
Source: Nature Communications
Authors: Douglas S. M. Ferreira, Katie McLennan, Calum Diamond, Melanie Vollmar, Wasim Kiyani, D. Sean Froese, Jola Kopec, Henry J. Bailey, Rod Chalk, Arnaud Baslé, Jonathan M. Elkins, Jesse A. Coker, Wyatt W. Yue, Thomas J. McCorvie
Language: English
Subfield: Nutrition and Dietetics
Field: Nursing
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $6,990
Funders: Pfizer, Genome Canada, Wellcome Trust, Diamond Light Source, European Federation of Pharmaceutical Industries and Associations, Ontario Ministry of Economic Development and Innovation, University of Oxford, Newcastle University, Fundação de Amparo à Pesquisa do Estado de São Paulo, Ministero dello Sviluppo Economico, Novartis Pharma, Medical Research Council, Biotechnology and Biological Sciences Research Council
Awards: G1651692390, G1812239805, A regional cryoEM facility at the University of York, Open access research to promote drug discovery., G2592000683, G2939136323, G3067317523, Cells to Molecules: Structural EM at Newcastle University, G339059223, G3603401286, A community based training programme for cryo-electron microscopy, G4946031807, A regional cryoEM facility at the University of York, G5753071127, G6502606440, Open access research to promote drug discovery., G7669079602, G774547617, A community based training programme for cryo-electron microscopy, G7889860134, G8210555217, G8328638188, G8608118112, G9000011233, G9000245716
OpenAlex ID: W4416091531