Mutant-selective topologic conversion facilitates selective degradation of a pathogenic prion isoform

Area of Science:

• Cellular Biology
• Protein Folding and Degradation
• Neurodegenerative Diseases

Background:

• Protein translocation across the endoplasmic reticulum (ER) membrane can yield topologically aberrant variants.
• Accumulation of these unnatural protein variants can lead to cellular toxicity (proteotoxicity).
• The functional consequences of regulated topological rearrangement during protein import remain unclear.

Purpose of the Study:

• To investigate the functional significance of translocational regulation in protein import.
• To demonstrate the role of mutant-selective topologic conversion (MSTC) in managing misfolded prion protein.
• To elucidate how MSTC contributes to the degradation of the membrane-anchored prion protein isoform (ctmPrP).

Main Methods:

• Investigated cotranslational translocation of prion protein variants.
• Utilized mutant analysis to identify key domains involved in topological conversion.
• Assessed degradation pathways (proteasome-dependent) and their impact on protein accumulation.
• Examined the role of the N-terminal polycationic cluster in MSTC.

Main Results:

• Mutant-selective topologic conversion (MSTC) cotranslationally generates the specific topology of ctmPrP.
• MSTC facilitates the rapid, proteasome-dependent degradation of ctmPrP from the ER.
• Cytosolic exposure of the N-terminal polycationic cluster is crucial for MSTC-mediated degradation, acting as an ER-associated degradation degron.
• Bypassing MSTC significantly delays ctmPrP degradation, leading to increased prion proteotoxicity.

Conclusions:

• Topological rearrangement via MSTC is a regulated protein quality control mechanism.
• MSTC ensures the selective degradation of ctmPrP, preventing its accumulation and subsequent proteotoxicity.
• This process safeguards the secretory pathway from misfolded prion proteins.