Hsp104

Hsp104 is a cytosolic heat shock protein found in Saccharomyces cerevisiae and other fungi. It belongs to the Hsp100/Clp family of AAA+ ATPases and functions as a molecular disaggregase, remodeling protein aggregates in cooperation with Hsp70 and Hsp40 chaperones. Hsp104 is a key determinant of yeast thermotolerance, enabling survival after severe heat stress.

Mechanism and interactions: Hsp104 forms a homo-hexameric ring with a central pore. Each subunit contains an N-terminal substrate-recognition domain and two AAA+ ATPase domains (D1 and D2). ATP hydrolysis drives conformational cycles that unfold polypeptides and thread them through the central channel. The disaggregase cooperates with Hsp70 systems, such as Ssa1/2, and Hsp40 co-chaperones like Ydj1 or Sis1, to capture, solubilize, and refold or direct substrates for degradation.

Biology and prions: In yeast, Hsp104 is essential for the propagation of certain prions, notably [PSI+] and [URE3]. Loss of Hsp104 function impairs prion maintenance, while altered levels of Hsp104 can cure prions in some contexts. This reflects its crucial role in managing aggregated and misfolded proteins that influence heritable protein states.

Distribution and evolution: The HSP104 gene is heat-inducible and encodes a cytosolic protein. Hsp104 is widespread in fungi and is related to the bacterial ClpB; animals generally lack an endogenous Hsp104, though researchers have explored heterologous expression in mammalian systems. Some plants and other organisms also possess Hsp104-like disaggregases.

Research and potential applications: Hsp104 has attracted attention for its ability to disaggregate amyloid and other protein aggregates. Engineered variants have shown activity against several amyloid proteins in model systems, prompting interest in therapeutic approaches for neurodegenerative diseases, though practical delivery and specificity remain challenges.