Sequence features governing aggregation or degradation of prion-like proteins

Area of Science:

• Biochemistry
• Molecular Biology
• Neuroscience

Background:

• Protein aggregation and impaired clearance are implicated in neurodegenerative disorders like Alzheimer's and prion diseases.
• Protein quality control systems target and degrade aggregation-prone proteins, a process prions must evade.

Purpose of the Study:

• To investigate sequence features that dictate degradation versus aggregation of prion domains.
• To explore how amino acid composition affects the interplay between protein aggregation and degradation.

Main Methods:

• Developed a genetic screen in yeast to analyze prion domains from Sup35, hnRNPA1, and hnRNPA2.
• Assessed the impact of specific amino acids (aliphatic, aromatic) on aggregation and degradation propensities.

Main Results:

• Aggregation and degradation propensities can be uncoupled; not all aggregation-promoting residues trigger degradation.
• Large aliphatic residues enhanced degradation of glycine-rich domains but promoted aggregation without degradation for aromatic residues.
• Aliphatic residues' degradation-promoting effect was suppressed in glutamine/asparagine-rich domains, increasing spontaneous prion formation.

Conclusions:

• Specific amino acid properties differentially regulate protein aggregation and degradation.
• Yeast prion domains may possess underappreciated activities that suppress degradation.
• Findings provide insights into how aggregation-prone proteins evade cellular degradation systems, relevant to prion disease pathogenesis.