Structural basis for a filamentous morpheein model of human cystathionine beta-synthase.

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.