Structural basis for a filamentous morpheein model of human cystathionine beta-synthase
DOKPE
- Mohammed, Inayathulla University of Lausanne
- Mijatovic, Ela University of Fribourg
- Philipp, Thilo Magnus University of Fribourg
- Janickova, Lucia University of Fribourg
- Ascencao, Kelly University of Fribourg
- Asturias, Francisco J University of Colorado Anschutz Medical Campus, Aurora, CO, USA
- Martinez-Cruz, Luis Alfonso Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Derio, Spain
- Csaba, Szabo University of Fribourg
- Stahlberg, Henning Ecole Polytechnique Federale de Lausanne
- Majtan, Tomas University of Fribourg
- 2026
Published in:
- Nature Communications. - Springer Science and Business Media LLC. - 2026, vol. 17, no. 1
Cryo-electron microscopy
Hydrolases
Enzyme mechanisms
Metalloproteins
Oligomerization
Homocysteine
Hydrogen sulfide
English
Human cystathionine beta-synthase (CBS) is a vital enzyme that regulates sulfur amino acid metabolism, hydrogen sulfide production, and cellular redox balance. Using a multidisciplinary approach, we demonstrate that CBS functions as a filamentous morpheein, with its stability, turnover, and activity governed by dynamic quaternary structural transitions. Three distinct filamentous assemblies were resolved by cryo-EM and are mediated by the oligomerization loop (residues 516-525): (i) ligand-free trans-dimers that form trans-basal filaments with basal stability and activity, (ii) adenosylornithine-bound cis-dimers that assemble into stabilized cis-basal filaments and (iii) S-adenosylmethionine-bound allo-dimers, which, together with cis-dimers, form highly stable, allo-activated stacked filaments. These reversible filamentous assemblies redefine CBS biology by integrating oligomerization and allosteric regulation within a morpheein framework. These findings provide a transformative perspective on CBS function and open avenues for pharmacological targeting of dysregulated CBS in various diseases including homocystinuria, cancer, and Down syndrome.
- Faculty
- Faculté des sciences et de médecine
- Department
- Section de médecine
- Language
-
- English
- Classification
- Pharmacology, therapeutics, toxicology
- Other electronic version
- License
-
CC BY
- Open access status
- gold
- Identifiers
-
- DOI 10.1038/s41467-026-73198-7
- ISSN 2041-1723
- Persistent URL
- https://folia.unifr.ch/unifr/documents/336575
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