8S5L

Full-length human cystathionine beta-synthase, basal state, partially degraded tetramer

8S5L の概要

• エントリーDOI: 10.2210/pdb8s5l/pdb
• EMDBエントリー: 19739
• 分子名称: Cystathionine beta-synthase, PROTOPORPHYRIN IX CONTAINING FE, PYRIDOXAL-5'-PHOSPHATE, ... (4 entities in total)
• 機能のキーワード: filament, allostery, transferase
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 246426.29

構造登録者

McCorvie, T.J.,Yue, W.W. (登録日: 2024-02-23, 公開日: 2024-04-17)

主引用文献

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

実験手法

ELECTRON MICROSCOPY (3.8 Å)