Architecture and regulation of filamentous human cystathionine beta-synthase

Abstract

Cystathionine beta-synthase (CBS) is an essential metabolic enzyme across all domains of life involved in the production of glutathione, cysteine, and hydrogen sulphide1-4. Human CBS appends to its conserved catalytic domain a regulatory domain that modulates activity by S-adenosyl-L-methionine (SAM) and promotes oligomerization5-12, however the molecular basis is unknown. 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 molecule of SAM 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.