Generalizable Compositional Features Influencing the Proteostatic Fates of Polar Low-Complexity Domains.

Protein aggregation is associated with a growing list of human diseases. A substantial fraction of proteins in eukaryotic proteomes constitutes a proteostasis network-a collection of proteins that work together to maintain properly folded proteins. One of the overarching functions of the proteostasis network is the prevention or reversal of protein aggregation. How proteins aggregate in spite of the anti-aggregation activity of the proteostasis machinery is incompletely understood. Exposed hydrophobic patches can trigger degradation by the ubiquitin-proteasome system, a key branch of the proteostasis network. However, in a recent study, we found that model glycine (G)-rich or glutamine/asparagine (Q/N)-rich prion-like domains differ in their susceptibility to detection and degradation by this system. Here, we expand upon this work by examining whether the features controlling the degradation of our model prion-like domains generalize broadly to G-rich and Q/N-rich domains. Experimentally, native yeast G-rich domains in isolation are sensitive to the degradation-promoting effects of hydrophobic residues, whereas native Q/N-rich domains completely resist these effects and tend to aggregate instead. Bioinformatic analyses indicate that native G-rich domains from yeast and humans tend to avoid degradation-promoting features, suggesting that the proteostasis network may act as a form of selection at the molecular level that constrains the sequence space accessible to G-rich domains. However, the sensitivity or resistance of G-rich and Q/N-rich domains, respectively, was not always preserved in their native protein contexts, highlighting that proteins can evolve other sequence features to overcome the intrinsic sensitivity of some LCDs to degradation.

Atypical structural tendencies among low-complexity domains in the Protein Data Bank proteome.

A variety of studies have suggested that low-complexity domains (LCDs) tend to be intrinsically disordered and are relatively rare within structured proteins in the Protein Data Bank (PDB). Although LCDs are often treated as a single class, we previously found that LCDs enriched in different amino acids can exhibit substantial differences in protein metabolism and function. Therefore, we wondered whether the structural conformations of LCDs are likewise dependent on which specific amino acids are enriched within each LCD. Here, we directly examined relationships between enrichment of individual amino acids and secondary structure tendencies across the entire PDB proteome. Secondary structure tendencies varied as a function of the identity of the amino acid enriched and its degree of enrichment. Furthermore, divergence in secondary structure profiles often occurred for LCDs enriched in physicochemically similar amino acids (e.g. valine vs. leucine), indicating that LCDs composed of related amino acids can have distinct secondary structure tendencies. Comparison of LCD secondary structure tendencies with numerous pre-existing secondary structure propensity scales resulted in relatively poor correlations for certain types of LCDs, indicating that these scales may not capture secondary structure tendencies as sequence complexity decreases. Collectively, these observations provide a highly resolved view of structural tendencies among LCDs parsed by the nature and magnitude of single amino acid enrichment.