Cells respond to environmental changes by toggling metabolic pathways, preparing for homeostasis, and anticipating future stresses. For example, in Saccharomyces cerevisiae, carbon stress-induced gluconeogenesis is terminated upon glucose availability, a process that involves the multiprotein E3 ligase GID^SR4 recruiting N termini and catalyzing ubiquitylation of gluconeogenic enzymes. Here, genetics, biochemistry, and cryoelectron microscopy define molecular underpinnings of glucose-induced degradation. Unexpectedly, carbon stress induces an inactive anticipatory complex (GID^Ant), which awaits a glucose-induced substrate receptor to form the active GID^SR4. Meanwhile, other environmental perturbations elicit production of an alternative substrate receptor assembling into a related E3 ligase complex. The intricate structure of GID^Ant enables anticipating and ultimately binding various N-degron-targeting (i.e., "N-end rule") substrate receptors, while the GID^SR4 E3 forms a clamp-like structure juxtaposing substrate lysines with the ubiquitylation active site. The data reveal evolutionarily conserved GID complexes as a family of multisubunit E3 ubiquitin ligases responsive to extracellular stimuli.

• PMID: 31708416
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Journal Article | Research Support, Non-U.S. Gov't

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Qiao S, Langlois CR, Chrustowicz J, Sherpa D, Karayel O, Hansen FM, Beier V, von Gronau S, Bollschweiler D, Schäfer T, ... Show all

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