HSP90: A Molecular Chaperone with Diverse Functions

HSP90 (Heat Shock Protein 90) is a major molecular chaperone that contributes to protein folding, maturation, and degradation in cells. This versatile protein is involved in various cellular processes, including signal transduction, protein trafficking, chromatin remodeling, and DNA repair. Here are some key points to know about HSP90:

  • Structure and function: HSP90 is a homodimeric protein that forms a large complex with co-chaperones, client proteins, and other regulatory factors. It binds to hydrophobic patches on client proteins and uses ATP hydrolysis to induce conformational changes and promote their stability and activity. HSP90 has two domains, N-terminal and C-terminal, and several subfamilies (HSP90α, HSP90β, GRP94, TRAP1, and others) with distinct tissue expression and client specificities.
  • Regulation and modulation: HSP90 is subject to various post-translational modifications, such as phosphorylation, acetylation, ubiquitination, and SUMOylation, that affect its stability, activity, and interaction with co-chaperones and clients. In addition, many small molecules and natural compounds have been identified as HSP90 inhibitors or modulators, with potential therapeutic applications in cancer, neurodegeneration, and other diseases. The most famous example is geldanamycin and its derivatives, which bind to the ATP-binding pocket of HSP90 and disrupt its function.
  • Client proteins and biological roles: HSP90 has been shown to interact with a wide range of client proteins, including oncogenic kinases (e.g., HER2, EGFR, ALK, BRAF), transcription factors (e.g., HIF-1α, NF-κB, AR, GR), steroid hormone receptors (e.g., ER, PR, AR), and stress-responsive proteins (e.g., p53, AKT, caspases). By regulating the folding, stability, and activity of these proteins, HSP90 can influence many cellular processes, such as cell proliferation, apoptosis, differentiation, and immune responses. HSP90 is also involved in protein quality control and clearance, through its interaction with the proteasome and autophagy pathways.
  • Clinical implications and challenges: HSP90 has attracted much attention as a promising target for cancer therapy, given its essential role in many oncogenic pathways and its high expression in tumor cells compared to normal cells. However, the complexity and redundancy of HSP90 regulation and functions pose challenges for the development of specific and effective inhibitors. Some of the issues include off-target effects, toxicity, resistance, and patient selection. Nevertheless, ongoing preclinical and clinical studies are exploring the potential of HSP90 inhibitors and combinations with other therapies in various cancer types.

In summary, HSP90 is a crucial molecular chaperone that plays diverse and dynamic roles in cellular physiology and pathology. Its structural and functional features, regulation and modulation, client proteins and biological functions, as well as clinical implications and challenges, make it a fascinating and challenging protein for basic and translational research.