The non-prion SUP35 preexists in large chaperone-containing molecular complexes

Area of Science:

• Biochemistry
• Molecular Biology
• Neurodegenerative Diseases

Background:

• Prions are misfolded proteins causing fatal neurodegenerative diseases with no current treatments.
• The accepted model posits soluble prion-forming proteins exist as monomers, not large complexes.
• Understanding the structure of non-prion proteins is crucial for developing therapeutic strategies.

Purpose of the Study:

• To investigate the molecular state of the non-prion form of the yeast prion-forming protein SUP35.
• To determine if non-prion proteins associate with molecular chaperones and other prion-forming proteins.
• To challenge the existing model of soluble prion protein structure.

Main Methods:

• Analytical ultracentrifugation with fluorescent detection was employed.
• The size distribution of soluble SUP35 complexes was analyzed.
• The association of chaperones and other prion-forming proteins within these complexes was assessed.

Main Results:

• The non-prion form of SUP35 exists in various discrete soluble complexes (19S to 200S).
• These complexes stoichiometrically associate with molecular chaperones, notably HSP70 proteins.
• The prion-forming protein RNQ1 was also found within these non-prion SUP35 complexes.

Conclusions:

• The non-prion forms of SUP35 and RNQ1 can form large, chaperone-associated complexes, contrary to prior models.
• This suggests that aggregation-prone proteins may exist in complex forms even in their normal state.
• These findings have significant implications for understanding the pathogenesis of protein aggregation diseases.