Aggregation and degradation scales for prion-like domains: sequence features and context weigh in
Protein aggregation in vivo is generally combated by extensive proteostatic defenses. Many proteostasis factors specifically recognize aggregation-prone features and re-fold or degrade the targeted protein. However, protein aggregation is not uncommon, suggesting that some proteins employ evasive strategies to aggregate in spite of the proteostasis machinery. Therefore, in addition to understanding the inherent aggregation propensity of protein sequences, it is important to understand how these sequences affect proteostatic recognition and regulation in vivo. In a recent study, we used a genetic mutagenesis and screening approach to explore the aggregation or degradation promoting effects of the canonical amino acids in the context of G-rich and Q/N-rich prion-like domains (PrLDs). Our results indicate that aggregation propensity scales are strongly influenced by the interplay between specific PrLD features and proteostatic recognition. Here, we briefly review these results and expand upon their potential implications. In addition, a preliminary exploration of the yeast proteome suggests that these proteostatic regulation heuristics may influence the compositional features of native G-rich and Q/N-rich domains in yeast. These results improve our understanding of the features affecting the aggregation and proteostatic regulation of prion-like domains in a cellular context, and suggest that the sequence space for native prion-like domains may be shaped by proteostatic constraints.
KeywordsProteostasis Protein aggregation Prion Prion-like Protein degradation Low complexity domain
This work was supported by a grant from the National Science Foundation (MCB-1817622) to E.D.R.
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