The molecular chaperone Hsp90 is one of the most abundant proteins in the cell with 1–2% of the total soluble cell protein . It occurs ubiquitously in eubacteria and all classes of eukaryotes . However , it seems to be absent in archaea . While cytoplasmic Hsp90 is essential for viability under all conditions in eukaryotes, the bacterial homolog HtpG is not essential under non-stress conditions. In mammalian cells, two genes code for cytosolic Hsp90 homologs. The first indication that Hsp90 is a heat shock protein came from studies with monkey cells and the fruit fly Drosophila melanogaster , which showed increased Hsp90 expression under non-physiological conditions.
Structural properties of Hsp90
Hsp90 consists of three domains: a highly conserved amino-terminal ATPase domain, a middle domain and a carboxy-terminal dimerization domain.
The Hsp90 ATPase activity
The ATP hydrolysis appears crucial for the function of Hsp90 in vivo to be because mutant can not hydrolyze ATP, can not perform the vital functions of Hsp90. The crystal structure of the amino-terminal domain of Hsp90 in complex with ATP showed that - in contrast to most other ATP-hydrolyzing proteins - ATP is bound in an unusually kinked conformation.
Inhibitors - Hsp90 as a drug target
Geldanamycin and the related herbimycin A are ansamycins from fungi that have antitumor activity. Geldanamycin binds to the amino terminal domain of Hsp90 as a competitive inhibitor of ATP . Geldanamycin's affinity for Hsp90 is approximately 500 times higher than that of ATP. Radicicol (or Monorden) is a macrolactone from a fungus and binds to Hsp90 with nanomolar affinity. Crystal studies have shown that radicicol also binds in the amino-terminal ATP binding pocket of Hsp90. The fact that completely different classes of natural substances can bind to the ATP binding pocket of Hsp90 with high specificity and affinity and the identification of a number of antitumor proteins as Hsp90 substrates have led to the idea that Hsp90 could be used as a drug target . First clinical studies with human-compatible Geldanamycin derivatives, such as B. 17-AAG (17-allylamino-17-demethoxygeldanamycin), which shows strong antitumor activity against a number of different types of cancer in nanomolar concentrations , are already carried out in numerous countries.
Function of Hsp90
The molecular chaperones Hsp70 and Hsp90 are responsible for the folding and activation of many substrate proteins . The most important representatives of Hsp70 and Hsp90 dependent proteins include steroid hormone receptors, transcription factors, kinases and the tumor suppressor protein p53 . Hsp70 and Hsp90 form a multichaperone complex in which both are linked by a third protein (Hop). The interplay and interaction of these two chaperone machines is of great importance for the survival of cells and organisms.
- H. Wegele, L. Muller, J. Buchner: Hsp70 and Hsp90 - a relay team for protein folding. In: Rev Physiol Biochem Pharmacol . 151, 2004, pp. 1-44.