Structural basis of PP2A activation by PTPA, an ATP-dependent activation chaperone.
Structural basis of PP2A activation by PTPA, an ATP-dependent activation chaperone.
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作者：
蛋白磷酸酶2A（PP 2A）催化亚基的适当活化是复杂PP 2A调节的中心，对细胞功能的广泛方面至关重要。PP 2A与PP 2A磷酸酶激活剂（PTPA）和ATPγS结合的晶体结构表明，PTPA与PP 2A活性位点周围的结构元件和ATP的腺嘌呤部分广泛接触。PTPA结合稳定了激活所需的apo-PP 2A的蛋白质折叠，并使ATP磷酰基定向以直接结合到PP 2A活性位点。这允许ATP调节PP 2A活性位点的金属结合偏好，并利用PP 2A活性位点进行ATP水解。在体外，ATP选择性地和显著地增强内源性催化金属离子的结合，这需要ATP水解，并且对于获得pSer/Thr特异性磷酸酶活性至关重要。此外，PP 2A和ATP结合都是PTPA在细胞增殖和存活中的功能所必需的。我们的研究结果表明PTPA在PP 2A活化中的新机制具有结构经济性和独特的ATP结合口袋，可能成为特异性治疗靶点。
Proper activation of protein phosphatase 2A (PP2A) catalytic subunit is central for the complex PP2A regulation and is crucial for broad aspects of cellular function. The crystal structure of PP2A bound to PP2A phosphatase activator (PTPA) and ATPγS reveals that PTPA makes broad contacts with the structural elements surrounding the PP2A active site and the adenine moiety of ATP. PTPA-binding stabilizes the protein fold of apo-PP2A required for activation, and orients ATP phosphoryl groups to bind directly to the PP2A active site. This allows ATP to modulate the metal-binding preferences of the PP2A active site and utilize the PP2A active site for ATP hydrolysis. In vitro, ATP selectively and drastically enhances binding of endogenous catalytic metal ions, which requires ATP hydrolysis and is crucial for acquisition of pSer/Thr-specific phosphatase activity. Furthermore, both PP2A- and ATP-binding are required for PTPA function in cell proliferation and survival. Our results suggest novel mechanisms of PTPA in PP2A activation with structural economy and a unique ATP-binding pocket that could potentially serve as a specific therapeutic target.
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DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K
影响因子：
3.5
作者：
Nishito, Y;Usui, H;Takeda, M
通讯作者：
Takeda, M
影响因子：
4.8
作者：
Lee, Jocelyn A.;Pallas, David C.
通讯作者：
Pallas, David C.
影响因子：
16.6
作者：
通讯作者：
--
影响因子：
2.9
作者：
CAYLA, X;GORIS, J;MERLEVEDE, W
通讯作者：
MERLEVEDE, W