EMD-19736

Single-particle
3.1 Å
EMD-19736 Deposition: 23/02/2024
Map released: 17/04/2024
Last modified: 17/04/2024
Overview 3D View Sample Experiment Validation Volume Browser Additional data Links
Overview 3D View Sample Experiment Validation Volume Browser Additional data Links

EMD-19736

Full-length human cystathionine beta-synthase with C-terminal 6xHis-tag, basal state, single particle reconstruction

EMD-19736

Single-particle
3.1 Å
EMD-19736 Deposition: 23/02/2024
Map released: 17/04/2024
Last modified: 17/04/2024
Overview 3D View Sample Experiment Validation Volume Browser Additional data Links
Sample Organism: Homo sapiens
Sample: Helical assembly of full-length human cystathionine beta-synthase in the basal state
Fitted models: 8s5i (Avg. Q-score: 0.396)

Deposition Authors: McCorvie TJ , Yue WW
Architecture and regulation of filamentous human cystathionine beta-synthase.
PUBMED: 38575566
DOI: doi:10.1038/s41467-024-46864-x
ISSN: 2041-1723
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.