INVESTIGADORES
GALIGNIANA Mario Daniel
congresos y reuniones científicas
Título:
Relevance of binding stoiquiometry of TPR-domain co-chaperones to Hsp90 in the regulation of biological processes of the cell
Autor/es:
MAZAIRA GI, LAGADARI M, ERLEJMAN AG, GALIGNIANA MD
Lugar:
Montevideo
Reunión:
Conferencia; First International Conference of the South American Chapter of the Cell Stress Society International; 2014
Resumen:
Hsp90 is the major soluble protein of the cell. Most of the Hsp90 population is primarily cytoplasmic and a small fraction is present in the nucleus, where it shows several structural and functional properties. Hsp90 is a homodimer, and each protomer contains three flexibly linked regions ¾ the NT-domain or ATP-binding domain, the M-domain, and the CT-domain or dimerization domain. The latter also shows a conserved MEEVD motif that serves as the docking site for 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, the original value of one TPR protein bound per dimer of Hsp90 is the most likely. This early finding 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 associated to Hsp90 via that TPR clamp. Here we will discuss the biological relevance of the Hsp90-TPR protein stoiquiometry using various models such as the functional regulation of steroid receptors, the telomerase activity in tumor cells, the nuclear retention of transcription factors by the nucleoskeleton arrangement, and molecular events related to the neurodifferention process. In all of them, the biological properties shown by the chaperone heterocomplexes in the cell support the existence of a single TPR protein associated to Hsp90 dimers, which can be dynamically exchanged by other TPR protein on mutually exclusive fashion. In view of the great number and relevance of signalling cascades and cellular events affected by that protein-protein interaction, the potential therapeutic use of drugs that may affect the Hsp90-TPR protein interaction will also be analyzed.