Analysis of Hsp90 cochaperone interactions reveals a novel mechanism for TPR protein recognition

Biochemistry
Ahmed ChadliDavid Toft

Abstract

The chaperone Hsp90 is required for the appropriate regulation of numerous key signaling molecules, including the progesterone receptor (PR). Many important cochaperones bind Hsp90 through their tetratricopeptide repeat (TPR) domains. Two such proteins, GCUNC45 and FKBP52, assist PR chaperoning and are thought to interact sequentially with PR-Hsp90 complexes. TPR proteins bind to the C-terminal MEEVD sequence of Hsp90, but GCUNC45 has been shown also to bind to a novel site near the N-terminus. We now show that FKBP52 is also able to bind to this site, and that these two cochaperones act competitively, through Hsp90, to modulate PR activity. The N-terminal site involves noncontiguous amino acids within or near the ATP binding pocket of Hsp90. TPR interactions at this site are thus strongly regulated by nucleotide binding and Hsp90 conformation. We propose an expanded model for client chaperoning in which the coordinated use of TPR recognition sites at both N- and C-terminal ends of Hsp90 enhances its ability to coordinate interactions with multiple TPR partners.

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Citations

Dec 15, 2010·Cell Stress & Chaperones·Rudi Kenneth Allan, Thomas Ratajczak
Mar 19, 2011·Quarterly Reviews of Biophysics·Kristin A KrukenbergDavid A Agard
Feb 21, 2008·The Journal of Biological Chemistry·Ahmed ChadliDavid O Toft
May 24, 2011·The Journal of Biological Chemistry·Pheroze Joshi, Cheryl A Stoddart
Mar 28, 2009·International Journal of Molecular Sciences·Torah M Kachur, David B Pilgrim
May 13, 2009·The International Journal of Biochemistry & Cell Biology·Thomas RatajczakRudi K Allan
Jun 2, 2018·Oncotarget·Frederick Zhehao ZhangRoger Hoi-Fung Wong
Jul 28, 2011·Journal of Cellular Physiology·Brett NixonR John Aitken
Sep 4, 2015·Bioscience Reports·Elizabeth A BlackburnMalcolm D Walkinshaw

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