Architecture and regulation of filamentous human cystathionine beta-synthase

Thomas J. McCorvie (), Douglas Adamoski, Raquel A. C. Machado, Jiazhi Tang, Henry J. Bailey, Douglas S. M. Ferreira, Claire Strain-Damerell, Arnaud Baslé, Andre L. B. Ambrosio, Sandra M. G. Dias and Wyatt W. Yue ()
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Thomas J. McCorvie: University of Oxford
Douglas Adamoski: Brazilian Center for Research in Energy and Materials
Raquel A. C. Machado: Brazilian Center for Research in Energy and Materials
Jiazhi Tang: Newcastle University
Henry J. Bailey: University of Oxford
Douglas S. M. Ferreira: University of Oxford
Claire Strain-Damerell: University of Oxford
Arnaud Baslé: Newcastle University
Andre L. B. Ambrosio: University of Sao Paulo
Sandra M. G. Dias: Brazilian Center for Research in Energy and Materials
Wyatt W. Yue: University of Oxford

Nature Communications, 2024, vol. 15, issue 1, 1-14

Abstract: Abstract 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.

Date: 2024
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DOI: 10.1038/s41467-024-46864-x

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