Aggregation-prone Regions in HYPK Help It to Form Sequestration Complex for Toxic Protein Aggregates

Area of Science:

• Biochemistry
• Cell Biology
• Neuroscience

Background:

• Protein aggregates disrupt cellular homeostasis and are implicated in various diseases.
• Cellular mechanisms exist to prevent or mitigate protein aggregation.
• Huntingtin interacting protein K (HYPK) is investigated for its role in protein aggregation regulation.

Purpose of the Study:

• To characterize Huntingtin interacting protein K (HYPK) as a global regulator of protein aggregation.
• To elucidate the mechanism by which HYPK prevents toxic protein aggregation.
• To identify HYPK's interacting partners and its role in cellular physiology.

Main Methods:

• Screening for interacting partners of aggregation-prone proteins (Huntingtin97Qexon1, α-Synuclein-A53T, SOD1-G93A).
• Characterization of HYPK's self-oligomerization and aggregate formation.
• Analysis of HYPK's binding affinity to aggregation-prone versus non-aggregating proteins.

Main Results:

• HYPK acts as a global regulator, forming unique annular sequestration complexes to prevent toxic protein aggregation.
• HYPK preferentially binds aggregation-prone proteins, initiating sequestration complexes in the cytosol and on ribosomes.
• HYPK's C-terminal hydrophobic regions mediate its own aggregation and interaction with toxic protein aggregates.
• HYPK reduces cellular toxic protein levels, preventing aggregate formation and improving cell survival and physiology.

Conclusions:

• HYPK is a potent, evolutionarily conserved protein aggregation inhibitor.
• HYPK's unique mechanism involves sensing and sequestering toxic protein aggregates.
• HYPK holds therapeutic potential for protein aggregation-related disorders.