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

Area of Science:

• Molecular Biology
• Biochemistry
• Proteostasis Network Research

Background:

• Protein aggregation is implicated in numerous human diseases.
• The proteostasis network maintains protein health, including preventing aggregation.
• The mechanisms by which proteins aggregate despite proteostasis are not fully understood.

Purpose of the Study:

• To investigate if degradation sensitivities of model glycine (G)-rich and glutamine/asparagine (Q/N)-rich prion-like domains generalize to native domains.
• To explore how sequence features influence the interaction between intrinsically disordered domains and the ubiquitin-proteasome system.

Main Methods:

• Experimental analysis of native yeast G-rich and Q/N-rich domains in isolation.
• Bioinformatic analysis of G-rich domains from yeast and humans.
• Comparison of domain behavior in isolation versus native protein contexts.

Main Results:

• Native G-rich domains are sensitive to degradation triggered by hydrophobic residues.
• Native Q/N-rich domains resist degradation and tend to aggregate.
• Bioinformatic analysis shows G-rich domains avoid degradation-promoting features, suggesting selection by the proteostasis network.
• This sensitivity/resistance is not always maintained in native protein contexts, indicating evolved compensatory features.

Conclusions:

• The proteostasis network imposes constraints on the sequence space of G-rich domains.
• Q/N-rich domains exhibit intrinsic resistance to degradation, favoring aggregation.
• Proteins can evolve additional sequence features to modulate the degradation susceptibility of intrinsically disordered low-complexity domains (LCDs).