RELEVANCE OF THE HSP90-IMMUNOPHILIN CHAPERONE SYSTEM IN THE REGULATION OF BASIC BIOLOGICAL PROCESSES IN HEALTH AND DISEASE

GALIGNIANA MD

Conferencia; LXI Reunión Anual de SAIC; 2016

Hsp90 is the major soluble protein of the cell. Most of the Hsp90 population is primarily cytoplasmic, and a small fraction is also nuclear and plays several structural and functional roles. In the cell, Hsp90 is a homodimer. Each protomer contains three flexibly linked regions  the N-terminal domain (or ATP-binding domain), the middle M-domain, and the C-terminal domain or dimerization domain. The latter shows a conserved MEEVD motif that serves as the docking site for Hsp90 co-chaperones via a tetratricopeptide repeat (TPR) clamp. Although in some studies is still under discussion what the real stoiquiometry of the interaction between Hsp90 dimers and TPR-domain co-chaperones is, there is a general consensus that in the cell it is likely that there is only one TPR protein bound per dimer of Hsp90. This early finding of our laboratory was subsequently validated by the regulatory action observed for several biological properties of Hsp90 client proteins due to the functional exchange of high molecular weight immunophilins such as FKBP51 and FKBP52 associated to Hsp90 via that TPR clamp. Here we will discuss the biological relevance of the Hsp90-immunophilin heterocomplex in the regulation of several biological models such as the steroid receptor function in health and disease, its involvement in cancer development and progression, the regulation of telomerase activity, the ability to promote the nuclear retention of transcription factors by nucleoskeleton arrangement, and its role in cell differentiation. In all of these basic biological situations, the properties shown by the Hsp90-immunophilin chaperone heterocomplex in the cell supports the existence of a single Hsp90-binding immunophilin bound per Hsp90 dimer, which can be dynamically exchanged by other TPR-domain proteins in a mutually exclusive fashion. In view of the number and relevance of signalling cascades and cellular events affected by this heterocomplex, the potential use of drugs with therapeutic purposes that may affect the organization and function of such protein arrangement is currently assayed in clinical trials.