The molecular chaperone Hsp90 (Wegele et al. 2004) 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 Hsp90a showing 85% sequence identity to Hsp90b. There is also high homology to Hsp90 from lower eukaryotesand prokaryotes: yeast Hsp90 is 60% identical to human Hsp90a and HtpG is still 34% identical to human Hsp90a.
1 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.
2 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.
3 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.
4 Functional properties
In the mammalian system, the molecular chaperones Hsp70 and Hsp90 are involved in the foldingProtein folding is the process by which a protein assumes its functional shape or conformation. All protein molecules are simple unbranched chains of amino acids, but it is by coiling into a specific three-dimensional shape that they are able to perform t and maturation of key regulatory proteins, like steroid hormone receptorSteroid hormone receptors are intracellular receptors that perform signal transduction for steroid hormones. After binding to the ligand, receptors often form dimers and act as transcription factors, augmenting or suppressing transcription of particular gs, transcriptionTranscription may be one of the following: In linguistics, transcription is the conversion of spoken words into written language. In genetics, transcription is the process of copying DNA to RNA by an enzyme called RNA polymerase (RNAP). In music transcrip factors like the tumorTumor originally just meant "swelling", but the term is very often used to denote abnormal ( malignant or benign) growth of tissue. Malignant tumors ( cancer) invade and destroy neighboring tissues and can become metastatic. Benign tumors do not invade ne suppressor protein p53p53 also known as TP53 or tumor protein ( EC: ) is a gene that codes for a protein that regulates the cell cycle and hence functions as a tumor suppression. It is very important for cells in multicellular organisms to suppress cancer. P53 has been describ, and kinaseIn biochemistry, a kinase is a type of enzyme that transfers phosphate groups from, for example, ATP to a specified substrate or target; the process is termed " phosphorylation". Typically, the target is "activated" or "energized" by being phosphorylated.s, 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 HopSee Hop (plant) Hop (telecommunications) Viking name for what was possibly a part of the North American coast (See also Vinland).. The connection of and the interplay between the two chaperone machineries is of crucial importance for cell viability.
