Mohammed, Inayathulla Mijatovic, Ela Philipp, Thilo Magnus Janickova, Lucia Ascencao, Kelly Asturias, Francisco J Martinez-Cruz, Luis Alfonso Csaba, Szabo Stahlberg, Henning Majtan, Tomas 2026 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. application/pdf https://folia.unifr.ch/global/documents/336575 https://folia.unifr.ch/documents/336575/files/s41467-026-73198-7.pdf https://folia.unifr.ch/documents/336575/files/41467_2026_73198_moesm1_esm.pdf eng https://www.nature.com/articles/s41467-026-73198-7 info:eu-repo/semantics/altIdentifier/doi/10.1038/s41467-026-73198-7 info:eu-repo/semantics/altIdentifier/issn/2041-1723 info:eu-repo/semantics/openAccess CC BY Nature Communications. - Springer Science and Business Media LLC. - 2026, vol. 17, no. 1 Cryo-electron microscopy Hydrolases Enzyme mechanisms Metalloproteins Oligomerization Homocysteine Hydrogen sulfide info:eu-repo/classification/udc/615 Structural basis for a filamentous morpheein model of human cystathionine beta-synthase http://purl.org/coar/resource_type/c_6501