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Lookup NU author(s): Dr Thomas McCorvieORCiD, Dr Jiazhi TangORCiD, Dr Arnaud Basle, Professor Wyatt YueORCiD
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© The Author(s) 2024. Cystathionine beta-synthase (CBS) is an essential metabolic enzyme across all domains of life for the production of glutathione, cysteine, and hydrogen sulfide. Appended to the conserved catalytic domain of human CBS is a regulatory domain that modulates activity by S-adenosyl-L-methionine (SAM) and promotes oligomerisation. Here we show using cryo-electron microscopy that full-length human CBS in the basal and SAM-bound activated states polymerises as filaments mediated by a conserved regulatory domain loop. In the basal state, CBS regulatory domains sterically block the catalytic domain active site, resulting in a low-activity filament with three CBS dimers per turn. This steric block is removed when in the activated state, one SAM molecule binds to the regulatory domain, forming a high-activity filament with two CBS dimers per turn. These large conformational changes result in a central filament of SAM-stabilised regulatory domains at the core, decorated with highly flexible catalytic domains. Polymerisation stabilises CBS and reduces thermal denaturation. In PC-3 cells, we observed nutrient-responsive CBS filamentation that disassembles when methionine is depleted and reversed in the presence of SAM. Together our findings extend our understanding of CBS enzyme regulation, and open new avenues for investigating the pathogenic mechanism and therapeutic opportunities for CBS-associated disorders.
Author(s): McCorvie TJ, Adamoski D, Machado RAC, Tang J, Bailey HJ, Ferreira DSM, Strain-Damerell C, Basle A, Ambrosio ALB, Dias SMG, Yue WW
Publication type: Article
Publication status: Published
Journal: Nature Communications
Year: 2024
Volume: 15
Online publication date: 04/04/2024
Acceptance date: 13/03/2024
Date deposited: 12/09/2024
ISSN (electronic): 2041-1723
Publisher: Springer Nature
URL: https://doi.org/10.1038/s41467-024-46864-x
DOI: 10.1038/s41467-024-46864-x
Data Access Statement: The authors declare that the main data supporting the findings of this study are available within the article and Supplementary Information. EM maps and models generated in this study, of CBS basal state (EMD-19735, PDB 8S5H, EMD-19736, PDB 8S5I, EMD-19737, PDB 8S5J, EMD-19738, PDB 8S5K), degraded CBS tetramer (EMD-19739, PDB 8S5L) and CBS + SAM activated state (EMD-19740, PDB 8S5M, EMD-19741, EMD-19742), have been deposited to the Electron Microscopy Data Bank (EMDB) and Protein Data Bank (PDB). Other structures referenced in this article are indicated, including PDB ID 4COO, 4UUU, and 4PCU. Source data are provided with this paper.
PubMed id: 38575566
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