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TitleArchitecture and regulation of filamentous human cystathionine beta-synthase.
Journal, issue, pagesNat Commun, Vol. 15, Issue 1, Page 2931, Year 2024
Publish dateApr 4, 2024
AuthorsThomas 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 / Wyatt W Yue /
PubMed AbstractCystathionine 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 ...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.
External linksNat Commun / PubMed:38575566 / PubMed Central
MethodsEM (helical sym.) / EM (single particle)
Resolution3.1 - 4.1 Å
Structure data

19735

8s5h

EMDB-19735, PDB-8s5h:
Full-length human cystathionine beta-synthase with C-terminal 6xHis-tag, basal state, helical reconstruction
Method: EM (helical sym.) / Resolution: 3.7 Å

19736

8s5i

EMDB-19736, PDB-8s5i:
Full-length human cystathionine beta-synthase with C-terminal 6xHis-tag, basal state, single particle reconstruction
Method: EM (single particle) / Resolution: 3.1 Å

19737

8s5j

EMDB-19737, PDB-8s5j:
Full-length human cystathionine beta-synthase, basal state, helical reconstruction
Method: EM (helical sym.) / Resolution: 3.9 Å

19738

8s5k

EMDB-19738, PDB-8s5k:
Full-length human cystathionine beta-synthase, basal state, single particle reconstruction
Method: EM (single particle) / Resolution: 3.8 Å

19739

8s5l

EMDB-19739, PDB-8s5l:
Full-length human cystathionine beta-synthase, basal state, partially degraded tetramer
Method: EM (single particle) / Resolution: 3.8 Å

19740

8s5m

EMDB-19740, PDB-8s5m:
Full-length human cystathionine beta-synthase with C-terminal 6xHis-tag, SAM bound, activated state, helical reconstruction
Method: EM (helical sym.) / Resolution: 4.0 Å

EMDB-19741: Full-length human cystathionine beta-synthase with C-terminal 6xHis-tag, SAM bound, activated state, local helical reconstruction
Method: EM (helical sym.) / Resolution: 4.1 Å

EMDB-19742: Full-length human cystathionine beta-synthase with C-terminal 6xHis-tag, SAM bound, activated state, local single particle reconstruction
Method: EM (single particle) / Resolution: 4.1 Å

Chemicals

ChemComp-HEM:
PROTOPORPHYRIN IX CONTAINING FE

ChemComp-PLP:
PYRIDOXAL-5'-PHOSPHATE

ChemComp-SAM:
S-ADENOSYLMETHIONINE

Source
  • homo sapiens (human)
KeywordsTRANSFERASE / Filament / Allostery

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