Hsp90

From Academic Kids

The molecular chaperone Hsp90 is one of the most abundant proteins in unstressed cells. It is an ubiquitous molecular chaperone found in eubacteria and all branches of eukarya, but it is apparently absent in archaea. Whereas cytoplasmic Hsp90 is essential for viability under all conditions in eukaryotes, the bacterial homologue HtpG is dispensable under non heat stress conditions. In mammalian cells, there are two genes encoding cytosolic Hsp90 homologues, with the human Hsp90α showing 85% sequence identity to Hsp90β. There is also high homology to Hsp90 from lower eukaryotes and prokaryotes: yeast Hsp90 is 60% identical to human Hsp90α and HtpG is still 34% identical to human Hsp90α. Hsp90 is one of the heat shock proteins, and is upregulated in many cells in response to stress.

Contents

Structural properties of Hsp90

Hsp90 is an elongated dimer with a low dissociation constant. The quaternary structure is important for the ATPase activity and associated conformational changes. Hsp90 consists of three major domains: a highly conserved amino-terminal ATPase domain, a middle domain, and a carboxy-terminal dimerization domain.

The Hsp90 ATPase activity

ATP hydrolysis seems to be of crucial importance for Hsp90 function in vivo, because mutants that do not hydrolyze ATP do not support the functions of Hsp90 essential for viability. The crystal structure of the amino-terminal domain of Hsp90 in complex with ADP showed that, in contrast to most other ATP hydrolyzing proteins, ATP is bound in an unusually kinked conformation.

Inhibitors

Geldanamycin (GA) and the related Herbimycin A are fungal ansamycins exhibiting antitumor activity. GA binds to the aminoterminal domain of Hsp90 as a competitive inhibitor of ATP. The affinity of GA for Hsp90 is about 500-fold higher than that of ATP. Radicicol (or monorden) is an even more competitive inhibitor of ATP binding with nanomolar affinity. The ability of two quite distinct classes of natural compounds to bind to the ATP-binding site in Hsp90 with high specificity and affinity together with the identification of a number of key anticancer target proteins as Hsp90 clients has led to the idea of Hsp90 as an antitumor drug target. Target validation and clinical trials of geldanamycin derivatives are underway in several countries, e.g., the GA derivative 17-AAG (17-allylamino,17-demethoxygeldanamycin), which shows potent activity against several cancers at low nanomolar concentrations in early clinical trials.

Functional properties

In the mammalian system, the molecular chaperones Hsp70 and Hsp90 are involved in the folding and maturation of key regulatory proteins, like steroid hormone receptors, transcription factors like the tumor suppressor protein p53, and kinases, some of which are involved in cancer progression. Hsp70 and Hsp90 form a multichaperone complex, in which both are connected by a third protein called Hop. The connection of and the interplay between the two chaperone machineries is of crucial importance for cell viability. Hsp90 is strongly upregulated as part of the heat shock response, helping protect the cell from protein damage and interfering with apoptosis.

References

  • Wegele H, Muller L, Buchner J. (2004). Hsp70 and Hsp90 - a relay team for protein folding. Rev Physiol Biochem Pharmacol 151:1-44de:HSP90
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