Nguyen Minh T N, Knieß Robert A, Daturpalli Soumya, Le Breton Laura, Ke Xiangyu, Chen Xuemei, Mayer Matthias P
Zentrum für Molekulare Biologie der Universität Heidelberg (ZMBH), DKFZ-ZMBH-Alliance, D-69120, Heidelberg, Germany.
School of Public Health, Southern Medical University, Guangzhou, 510515, Guangdong, China.
J Mol Biol. 2017 Mar 10;429(5):732-752. doi: 10.1016/j.jmb.2017.01.011. Epub 2017 Jan 19.
The 90-kDa heat shock proteins (Hsp90s) assist the maturation of many key regulators of signal transduction pathways and cellular control circuits like protein kinases and transcription factors and chaperone their stability and activity. In this function, Hsp90s cooperate with some 30 cochaperones and they are themselves subject to regulation by numerous post-translational modifications. In vertebrates, two major isoforms exist in the cytosol, Hsp90α and Hsp90β, which share a high degree of sequence identity and are expressed in tissue- and environmental condition-dependent manner. We identified an isoform-specific phosphorylation site in human Hsp90β. This phosphorylation site seems to be linked to vertebrate evolution since it is not found in invertebrata but in all tetrapoda and many but not all fish species. We provide data suggesting that this phosphorylation is important for the activation of Hsp90 clients like glucocorticoid receptor and a protein kinase. Replacement of the phosphorylation site by glutamate affects the conformational dynamics of Hsp90 and interaction with the kinase-specific cochaperone Cdc37.
90千道尔顿热休克蛋白（Hsp90s）协助信号转导通路和细胞控制回路的许多关键调节因子成熟，如蛋白激酶和转录因子，并维持其稳定性和活性。在这一功能中，Hsp90s与约30种共伴侣蛋白协同作用，其自身也受到多种翻译后修饰的调控。在脊椎动物中，胞质溶胶中存在两种主要的异构体，即Hsp90α和Hsp90β，它们具有高度的序列同一性，并以组织和环境条件依赖的方式表达。我们在人Hsp90β中鉴定出一个异构体特异性磷酸化位点。该磷酸化位点似乎与脊椎动物的进化有关，因为它在无脊椎动物中未被发现，而在所有四足动物以及许多（但不是所有）鱼类中都存在。我们提供的数据表明，这种磷酸化对于激活Hsp90的客户蛋白（如糖皮质激素受体和一种蛋白激酶）很重要。用谷氨酸取代磷酸化位点会影响Hsp90的构象动力学以及与激酶特异性共伴侣蛋白Cdc37的相互作用。
