Conserved degronome features governing quality control associated proteolysis

Abstract

The eukaryotic proteome undergoes constant surveillance by quality control systems that either sequester, refold, or eliminate aberrant proteins by ubiquitin-dependent mechanisms. Ubiquitin-conjugation necessitates the recognition of degradation determinants, termed degrons, by their cognate E3 ubiquitin-protein ligases. To learn about the distinctive properties of quality control degrons, we performed an unbiased peptidome stability screen in yeast. The search identify a large cohort of proteome-derived degrons, some of which exhibited broad E3 ligase specificity. Consequent application of a machine-learning algorithm establishes constraints governing degron potency, including the amino acid composition and secondary structure propensities. According to the set criteria, degrons with transmembrane domain-like characteristics are the most probable sequences to act as degrons. Similar quality control degrons are present in viral and human proteins, suggesting conserved degradation mechanisms. Altogether, the emerging data indicate that transmembrane domain-like degron features have been preserved in evolution as key quality control determinants of protein half-life.

A mutational atlas for Parkin proteostasis

“…This revealed that most low abundance tiles overlapped with regions with a high-quality control degron probability (Fig. 4D ), confirming that these degrons contain the quality control degron features observed before 51 . Accordingly, when mapping the TSI onto the Parkin structure, most low-abundance tiles were found at buried positions (Supplementary Fig.…”

Defining the mechanisms and properties of post-transcriptional regulatory disordered regions by high-throughput functional profiling

“…To distinguish key functional residues, we created a light attention model that learns these additional repressive features from large protein language models. This model improved our activity predictions and provides a valuable framework for further understanding the molecular grammar of disordered sequences in broad regulatory programs, such as transcription activation domains and E3 degron signals 3,22,57,64 . These approaches also exemplify a strategy to understand the effects of sequence variants and mutations in disordered peptides, which have distinct behavior from folded domains and are less suited to structure-guided approaches.…”

C-terminal sequence stability profiling in Saccharomyces cerevisiae reveals protective protein quality control pathways

“…Recent studies with yeast PQC degrons have shown that in general an exposed stretch of hydrophobic amino acids without negative charges constitutes a degron ( 20 , 55 , 56 ) and that in mammalian cells similar rules apply ( 14 ). This is in agreement with the notion that hydrophobic amino acids are mostly embedded in the interior of globular proteins ( 57 ).…”

“…Negatively charged amino acids might act as stabilizing factors in protein sequences. It has been reported that the use of a negative amino acid at position −1 (exchange Q to E) within a degron sequence leads to substrate stabilization and loss of interaction with the mammalian ubiquitin–protein ligase TRIM7 ( 22 ) as well as that negatively charged amino acids are generally scarce in yeast degrons and counteract degradation signals when placed in the core of a degron ( 55 ). We observed aspartate at all six positions associated with stable variants.…”