Beschreibung:
<jats:p>Cells must have the ability to rapidly respond to environmental cues in order to adapt to changes in nutrient availability or stress. Cellular changes at the protein level can take many forms, including modification of the activity of previously existing proteins, synthesis of new proteins, and degradation of proteins that are no longer needed. Indeed, protein turnover by E3 ubiquitin ligases provides a rapid and irreversible mechanism for cellular response. For example, yeast cells starved for sugar require gluconeogenic production of glucose. However, upon glucose availability, this energetically expensive process must be terminated. The GID (
<jats:styled-content><jats:bold>G</jats:bold></jats:styled-content>lucose‐
<jats:styled-content><jats:bold>I</jats:bold></jats:styled-content>nduced
<jats:styled-content><jats:bold>D</jats:bold></jats:styled-content>egradation) E3 ligase plays a pivotal role in this process by targeting gluconeogenic enzymes, including Fbp1 and Mdh2, for degradation. However, the precise molecular mechanisms that govern the regulation of the GID ligase remain unclear.</jats:p><jats:p>To understand the mechanism of the active GID E3 complex, we combined <jats:italic>in vivo</jats:italic> studies in yeast cell biology and biochemistry with <jats:italic>in vitro</jats:italic> biochemical studies reconstituting the endogenous properties with recombinant proteins. We found that in response to sugar starvation, an inactive GID complex assembles in cells in anticipation of upcoming environmental changes. Following sugar availability, the GID complex is activated through the binding of its substrate receptor, Gid4, which allows the complex to recognize and ubiquitinate key gluconeogenic enzymes. Furthermore, the GID complex is not a singular complex, but is instead a family of multisubunit E3 ligases able to respond to a variety of cellular stresses through the incorporation of swappable substrate receptors.</jats:p>