Chadli Ahmed, Graham J Dinny, Abel M Greg, Jackson Twila A, Gordon David F, Wood William M, Felts Sara J, Horwitz Kathryn B, Toft David
Department of Biochemistry and Molecular Biology, Mayo Clinic, 200 First St. Southwest, Rochester, MN 55905, USA.
Mol Cell Biol. 2006 Mar;26(5):1722-30. doi: 10.1128/MCB.26.5.1722-1730.2006.
The hsp90 chaperoning pathway is a multiprotein system that is required for the production or activation of many cell regulatory proteins, including the progesterone receptor (PR). We report here the identity of GCUNC-45 as a novel modulator of PR chaperoning by hsp90. GCUNC-45, previously implicated in the activities of myosins, can interact in vivo and in vitro with both PR-A and PR-B and with hsp90. Overexpression and knockdown experiments show GCUNC-45 to be a positive factor in promoting PR function in the cell. GCUNC-45 binds to the ATP-binding domain of hsp90 to prevent the activation of its ATPase activity by the cochaperone Aha1. This effect limits PR chaperoning by hsp90, but this can be reversed by FKBP52, a cochaperone that is thought to act later in the pathway. These findings reveal a new cochaperone binding site near the N terminus of hsp90, add insight on the role of FKBP52, and identify GCUNC-45 as a novel regulator of the PR signaling pathway.
热休克蛋白90（hsp90）伴侣蛋白途径是一个多蛋白系统，许多细胞调节蛋白的产生或激活都需要该系统，包括孕激素受体（PR）。我们在此报告GCUNC-45作为hsp90介导的PR伴侣蛋白的新型调节剂的身份。GCUNC-45先前被认为与肌球蛋白的活性有关，它在体内和体外均可与PR-A和PR-B以及hsp90相互作用。过表达和敲低实验表明，GCUNC-45是促进细胞中PR功能的一个积极因素。GCUNC-45与hsp90的ATP结合域结合，以阻止共伴侣蛋白Aha1激活其ATP酶活性。这种作用限制了hsp90对PR的伴侣蛋白作用，但这可以被FKBP52逆转，FKBP52是一种被认为在该途径后期起作用的共伴侣蛋白。这些发现揭示了hsp90 N端附近一个新的共伴侣蛋白结合位点，加深了对FKBP52作用的理解，并确定GCUNC-45是PR信号通路的新型调节剂。
