Interconversion between Anticipatory and Active GID E3 Ubiquitin Ligase Conformations via Metabolically Driven...

Area of Science:

• Cellular biology
• Biochemistry
• Molecular genetics

Background:

• Cells dynamically adjust metabolic pathways in response to environmental cues.
• In Saccharomyces cerevisiae, glucose availability triggers the termination of carbon stress-induced gluconeogenesis.
• This process relies on the GIDSR4 E3 ligase complex to ubiquitylate gluconeogenic enzymes for degradation.

Purpose of the Study:

• To elucidate the molecular mechanisms underlying glucose-induced protein degradation.
• To investigate the structure and function of the GID E3 ligase complex.

Main Methods:

• Genetics
• Biochemistry
• Cryo-electron microscopy (cryo-EM)

Main Results:

• Carbon stress induces an inactive GID complex (GIDAnt) that awaits substrate receptor binding.
• Glucose availability leads to the formation of the active GIDSR4 E3 ligase.
• GIDAnt's structure facilitates binding to various N-end rule substrate receptors.
• The GIDSR4 E3 ligase forms a clamp-like structure for ubiquitylation.
• Evolutionarily conserved GID complexes are responsive to extracellular stimuli.

Conclusions:

• The GID E3 ligase complex functions as a sophisticated molecular machine for sensing and responding to environmental changes.
• This family of E3 ligases utilizes distinct subunit compositions to target specific substrates based on extracellular signals.
• The findings reveal a conserved mechanism for stimulus-responsive protein degradation in eukaryotes.