Yang Jing, Roe S Mark, Cliff Matthew J, Williams Mark A, Ladbury John E, Cohen Patricia T W, Barford David
Section of Structural Biology, The Institute of Cancer Research, Chester Beatty Laboratories, London, UK.
EMBO J. 2005 Jan 12;24(1):1-10. doi: 10.1038/sj.emboj.7600496. Epub 2004 Dec 2.
Protein phosphatase 5 (Ppp5) is a serine/threonine protein phosphatase comprising a regulatory tetratricopeptide repeat (TPR) domain N-terminal to its phosphatase domain. Ppp5 functions in signalling pathways that control cellular responses to stress, glucocorticoids and DNA damage. Its phosphatase activity is suppressed by an autoinhibited conformation maintained by the TPR domain and a C-terminal subdomain. By interacting with the TPR domain, heat shock protein 90 (Hsp90) and fatty acids including arachidonic acid stimulate phosphatase activity. Here, we describe the structure of the autoinhibited state of Ppp5, revealing mechanisms of TPR-mediated phosphatase inhibition and Hsp90- and arachidonic acid-induced stimulation of phosphatase activity. The TPR domain engages with the catalytic channel of the phosphatase domain, restricting access to the catalytic site. This autoinhibited conformation of Ppp5 is stabilised by the C-terminal alphaJ helix that contacts a region of the Hsp90-binding groove on the TPR domain. Hsp90 activates Ppp5 by disrupting TPR-phosphatase domain interactions, permitting substrate access to the constitutively active phosphatase domain, whereas arachidonic acid prompts an alternate conformation of the TPR domain, destabilising the TPR-phosphatase domain interface.
蛋白磷酸酶5（Ppp5）是一种丝氨酸/苏氨酸蛋白磷酸酶，在其磷酸酶结构域的N端包含一个调节性四肽重复（TPR）结构域。Ppp5在控制细胞对应激、糖皮质激素和DNA损伤反应的信号通路中发挥作用。其磷酸酶活性受到TPR结构域和C端亚结构域维持的自抑制构象的抑制。通过与TPR结构域相互作用，热休克蛋白90（Hsp90）和包括花生四烯酸在内的脂肪酸可刺激磷酸酶活性。在此，我们描述了Ppp5自抑制状态的结构，揭示了TPR介导的磷酸酶抑制以及Hsp90和花生四烯酸诱导的磷酸酶活性刺激的机制。TPR结构域与磷酸酶结构域的催化通道结合，限制了对催化位点的 access。Ppp5的这种自抑制构象由C端αJ螺旋稳定，该螺旋与TPR结构域上Hsp90结合凹槽的一个区域接触。Hsp90通过破坏TPR-磷酸酶结构域的相互作用来激活Ppp5，使底物能够 access 组成型活性磷酸酶结构域，而花生四烯酸促使TPR结构域形成另一种构象，使TPR-磷酸酶结构域界面不稳定。
