Hsp90 Breaks the Deadlock of the Hsp70 Chaperone System

Protein folding in the cell requires ATP-driven chaperone machines such as the conserved Hsp70 and Hsp90. It is enigmatic how these machines fold proteins. Here, we show that Hsp90 takes a key role in protein folding by breaking an Hsp70-inflicted folding block, empowering protein clients to fold on their own. At physiological concentrations, Hsp70 stalls productive folding by binding hydrophobic, core-forming segments. Hsp90 breaks this deadlock and restarts folding. Remarkably, neither Hsp70 nor Hsp90 alters the folding rate despite ensuring high folding yields. In fact, ATP-dependent chaperoning is restricted to the early folding phase. Thus, the Hsp70-Hsp90 cascade does not fold proteins, but instead prepares them for spontaneous, productive folding. This stop-start mechanism is conserved from bacteria to man, assigning also a general function to bacterial Hsp90, HtpG. We speculate that the decreasing hydrophobicity along the Hsp70-Hsp90 cascade may be crucial for enabling spontaneous folding

Hsp90 chaperone in disease

The molecular chaperone Hsp90 is at the heart of protein homeostasis control. A wide range of pathologies disturbs protein homeostasis, thus placing Hsp90 at the crossroads of many diseases. Here, we evaluate the impact of recent progress in understanding the molecular mechanism of Hsp90-client interactions and their role in disease. We discuss the role of Hsp90 for hormonal imbalances, cancer and neurodegenerative disorders. For each disease class we discuss implications of complexes in which Hsp90 binds to a paradigmatic client: the transcription factor Glucocorticoid Receptor, the kinase Cdk4 and the microtubule stabilizer Tau. The mechanistic insights allow us to elaborate on possible therapeutic intervention routes. Hsp90 is a druggable chaperone. Thus, understanding Hsp90 biology at molecular resolution offers an interesting approach to tackle protein-related diseases

Challenging Proteostasis: Role of the Chaperone Network to Control Aggregation-Prone Proteins in Human Disease

Protein homeostasis (Proteostasis) is essential for correct and efficient protein function within the living cell. Among the critical components of the Proteostasis Network (PN) are molecular chaperones that serve widely in protein biogenesis under physiological conditions, and prevent protein misfolding and aggregation enhanced by conditions of cellular stress. For Alzheimer’s, Parkinson’s, Huntington’s diseases and ALS, multiple classes of molecular chaperones interact with the highly aggregation-prone proteins amyloid-β, tau, α-synuclein, huntingtin and SOD1 to influence the course of proteotoxicity associated with these neurodegenerative diseases. Accordingly, overexpression of molecular chaperones and induction of the heat shock response have been shown to be protective in a wide range of animal models of these diseases. In contrast, for cancer cells the upregulation of chaperones has the undesirable effect of promoting cellular survival and tumor growth by stabilizing mutant oncoproteins. In both situations, physiological levels of molecular chaperones eventually become functionally compromised by the persistence of misfolded substrates, leading to a decline in global protein homeostasis and the dysregulation of diverse cellular pathways. The phenomenon of chaperone competition may underlie the broad pathology observed in aging and neurodegenerative diseases, and restoration of physiological protein homeostasis may be a suitable therapeutic avenue for neurodegeneration as well as for cancer

ESICM LIVES 2016: part two : Milan, Italy. 1-5 October 2016.

Meeting abstrac