Architecture and regulation of filamentous human cystathionine beta-synthase

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McCorvie, Thomas J. ; Adamoski, Douglas ; Machado, Raquel A. C. ; Tang, Jiazhi ; Bailey, Henry J. ; Ferreira, Douglas S. M. ; Strain-Damerell, Claire ; Basle, Arnaud ; Ambrosio, Andre L. B. ; Dias, Sandra M. G. ; Yue, Wyatt W.

• Document type: Journal article
• Source: NATURE COMMUNICATIONS; v. 15, n. 1, p. 14-pg., 2024-04-04.

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. Cystathionine beta-synthase is a conserved essential enzyme of one-carbon metabolism. Here, the authors show that the enzyme oligomerises to form filaments that undergo conformational and morphological changes in response to its activator S-adenosyl-L-methionine, the global methyl donor. (AU)

• FAPESP's process: 23/01388-4 - Identification of new enzymes capable of aggregating under conditions of nutrient deprivation and their role in tumor progression.
• Grantee: Raquel Arminda Martinez Machado
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 21/05726-6 - Metabolism in the microenvironment and the role of metabolic exchanges in tumor progression
• Grantee: Sandra Martha Gomes Dias
• Support Opportunities: Research Projects - Thematic Grants