8S5K

Full-length human cystathionine beta-synthase, basal state, single particle reconstruction

Summary for 8S5K

• Entry DOI: 10.2210/pdb8s5k/pdb
• EMDB information: 19738
• Descriptor: Cystathionine beta-synthase, PROTOPORPHYRIN IX CONTAINING FE (2 entities in total)
• Functional Keywords: filament, allostery, transferase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 8
• Total formula weight: 492776.52

Authors

McCorvie, T.J.,Yue, W.W. (deposition date: 2024-02-23, release date: 2024-04-17)

Primary citation

McCorvie, T.J.,Adamoski, D.,Machado, R.A.C.,Tang, J.,Bailey, H.J.,Ferreira, D.S.M.,Strain-Damerell, C.,Basle, A.,Ambrosio, A.L.B.,Dias, S.M.G.,Yue, W.W.
Architecture and regulation of filamentous human cystathionine beta-synthase.
Nat Commun, 15:2931-2931, 2024

PubMed 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.

PubMed: 38575566
DOI: 10.1038/s41467-024-46864-x

Experimental method

ELECTRON MICROSCOPY (3.8 Å)