Chadli Ahmed, Bruinsma Elizabeth S, Stensgard Bridget, Toft David
Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA.
Biochemistry. 2008 Mar 4;47(9):2850-7. doi: 10.1021/bi7023332. Epub 2008 Jan 23.
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.
伴侣蛋白Hsp90是众多关键信号分子（包括孕激素受体，PR）进行适当调控所必需的。许多重要的共伴侣蛋白通过其四肽重复序列（TPR）结构域与Hsp90结合。两种这样的蛋白，GCUNC45和FKBP52，协助PR伴侣功能，并且被认为与PR-Hsp90复合物依次相互作用。TPR蛋白与Hsp90的C末端MEEVD序列结合，但已表明GCUNC45也能与N末端附近的一个新位点结合。我们现在表明FKBP52也能够结合到这个位点，并且这两种共伴侣蛋白通过Hsp90竞争性地发挥作用，以调节PR活性。N末端位点涉及Hsp90的ATP结合口袋内或附近不连续的氨基酸。因此，该位点的TPR相互作用受到核苷酸结合和Hsp90构象的强烈调节。我们提出了一个扩展的客户伴侣模型，其中在Hsp90的N末端和C末端同时使用TPR识别位点增强了其协调与多个TPR伴侣相互作用的能力。
