Enhanced protein aggregation and/or impaired clearance of aggregates can lead to neurodegenerative disorders such as Alzheimer’s Disease, Huntington’s Disease, and prion diseases. Therefore, many protein quality control factors specialize in recognizing and degrading aggregation-prone proteins. Prions, which generally result from self-propagating protein aggregates, must therefore evade or outcompete these quality control systems in order to form and propagate in a cellular context. We developed a genetic screen in yeast that allowed us to explore the sequence features that promote degradation versus aggregation of a model glutamine/asparagine (Q/N)-rich prion domain from the yeast prion protein, Sup35, and two model glycine (G)-rich prion-like domains from the human proteins hnRNPA1 and hnRNPA2. Unexpectedly, we found that aggregation propensity and degradation propensity could be uncoupled in multiple ways. First, only a subset of classically aggregation-promoting amino acids elicited a strong degradation response in the G-rich prion-like domains. Specifically, large aliphatic residues enhanced degradation of the prion-like domains, whereas aromatic residues promoted prion aggregation without enhancing degradation. Second, the degradation-promoting effect of aliphatic residues was suppressed in the context of the Q/N-rich prion domain, and instead led to a dose-dependent increase in the frequency of spontaneous prion formation. Degradation suppression correlated with Q/N content of the surrounding prion domain, potentially indicating an underappreciated activity for these residues in yeast prion domains. Collectively, these results provide key insights into how certain aggregation-prone proteins may evade protein quality control degradation systems. Author summary Protein aggregation is associated with a variety of diseases, including Alzheimer’s disease and Amyotrophic Lateral Sclerosis. Cells possess a number of factors that can recognize aggregation-prone protein features and prevent aggregation. One common way this is achieved is through the pre-emptive degradation of aggregation-prone proteins. While considerable progress has been made in understanding how the amino acid sequence of a protein relates to intrinsic aggregation propensity, little is known about how aggregation-prone proteins avoid intracellular anti-aggregation systems. We used a genetic screen in yeast to define sequence features of aggregation-prone domains that lead to degradation or prion aggregation as it occurs in the context of eukaryotic protein quality control factors. Unexpectedly, we found that only a subset of aggregation-promoting amino acids could effectively stimulate degradation of an aggregation-prone domain. Furthermore, this degradation-promoting effect could be suppressed by classical prion domain features. Our results highlight the complex interplay between pre-emptive protein degradation and protein aggregation, and implicate the unusual composition of yeast prion domains in preventing their degradation.
【초록키워드】 Diseases, Genetic, Proteins, Alzheimer’s disease, Protein, Features, amino acids, Factors, Quality control, Degradation, yeast, Glutamine, Amino acid, cellular, Frequency, neurodegenerative disorders, Amyotrophic lateral sclerosis, lead, amino acid sequence, genetic screen, glycine, control systems, Factor, asparagine, domains, residue, domain, sequence, human proteins, complex interplay, aggregation, aggregate, second, clearance, aggregates, Lateral Sclerosis, neurodegenerative disorder, aliphatic, aromatic residues, hnRNPA1, while, enhanced, Prevent, feature, highlight, intrinsic, classical, occur, recognize, variety, correlated, promote, increase in, to define, recognizing, suppressed, evade, dose-dependent, elicited, subset, stimulate, promoted, eukaryotic, aromatic residue, human protein, protein quality control, 【제목키워드】 Protein, feature,