Interconversion between anticipatory and active GID E3 ubiquitin ligase conformations via metabolically-driven substrate receptor assembly

ABSTRACT: Cells respond to environmental changes by toggling metabolic pathways, preparing for homeostasis, and anticipating future stresses. For example, in Saccharomyces cerevisiae starvation-induced gluconeogenesis is terminated upon glucose availability, a process that involves the multiprotein E3 ligase, GIDSR4, recruiting N-termini and catalyzing ubiquitylation of gluconeogenic enzymes. Here, genetics, biochemistry, and cryo-electron microscopy define molecular underpinnings of glucose-induced degradation. Unexpectedly, starvation induces an inactive anticipatory complex (GIDAnt), which awaits a glucose-induced substrate receptor to form the active GIDSR4. Meanwhile, other environmental perturbations elicit production of an alternative substrate receptor assembling into a related E3 ligase. The unprecedented, intricate structure of GIDAnt enables anticipating and ultimately binding various N-end rule substrate receptors, while the GIDSR4 E3 forms a clamp-like structure juxtaposing substrate lysines with the ubiquitylation active site. The data reveal the evolutionarily conserved GID complex at the heart of a novel family of multisubunit N-end rule ubiquitin E3s responsive to extracellular stimuli.

INSTRUMENT(S):

ORGANISM(S): Saccharomyces Cerevisiae (baker's Yeast)

SUBMITTER: Mario Oroshi  

LAB HEAD: Brenda A Schulman

PROVIDER: PXD015396 | Pride | 2026-10-19

REPOSITORIES: Pride