Abstract
Misfolded proteins present an escalating deleterious challenge to cells over the course of their lifetime. One mechanism the cell possesses to prevent misfolded protein accumulation is their destruction by protein quality control (PQC) degradation systems. In eukaryotes, PQC degradation typically proceeds via multiple ubiquitin-protein ligases that act throughout the cell to ubiquitinate misfolded proteins for proteasome degradation. What the exact feature of misfolding that each PQC ubiquitin-protein ligase recognizes in their substrates remains an open question. Our previous studies of the budding yeast nuclear ubiquitin-protein ligase San1 indicated that it recognizes exposed hydrophobicity within its substrates, with the threshold of hydrophobicity equivalent to that of 5 contiguous hydrophobic residues. Here, we uncover an additional parameter: the nature of the exposed hydrophobicity that confers San1-mediated degradation correlates with significant protein insolubility. San1 particularly targets exposed hydrophobicity that leads to insolubility and aggregation above a certain threshold. Our studies presented here provide additional insight into the details of misfolded nuclear protein recognition and demonstrate that there is selectivity for the type of exposed hydrophobicity.
Highlights
San[1] is a ubiquitin-protein ligase that recognizes exposed hydrophobicity in misfolded nuclear proteins
San[1] Recognition of Hydrophobicity Correlates with Substrate Insolubility—Previously, we found that San[1] recognizes short hydrophobic peptides as degrons when fused to reporter proteins such as GFP possessing a nuclear localization sequence (GFPNLS) or the Gal[4] activating domain used in two
Because insolubility and aggregate formation are detrimental results of protein misfolding, we examined the in vivo solubility of GFPNLS-peptide fusions containing 3, 4, 5, 6, or 7 contiguous hydrophobic residues
Summary
San[1] is a ubiquitin-protein ligase that recognizes exposed hydrophobicity in misfolded nuclear proteins. A cellular compartment can contain multiple PQC ubiquitin-protein ligases, they generally do not target the same substrates (20, 22–26), indicating that the compartment-specific PQC ligases are, for the most part, not functionally redundant. The lack of functional redundancy suggests that each PQC ubiquitin-protein ligase might recognize a unique feature of misfolding in its substrates. This likely depends upon the specific cellular compartment and the spatial organization of the PQC ligases within that compartment. With this consideration in mind, it remains an open question as to which feature(s) of misfolding an individual PQC ubiquitin-protein ligase targets. We find that San[1] prefers particular types of hydrophobic residues within that window, and this preference can be explained by the strength of the residues’ ability to cause insolubility and aggregation
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