Yang Jing, Roe S Mark, Prickett Todd D, Brautigan David L, Barford David
Section of Structural Biology, Chester Beatty Laboratories, Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK.
Biochemistry. 2007 Jul 31;46(30):8807-15. doi: 10.1021/bi7007118. Epub 2007 Jul 6.
Physiological functions of protein phosphatase 2A (PP2A) are determined via the association of its catalytic subunit (PP2Ac) with diverse regulatory subunits. The predominant form of PP2Ac assembles into a heterotrimer comprising the scaffolding PR65/A subunit together with a variable regulatory B subunit. A distinct population of PP2Ac associates with the Tap42/alpha4 subunit, an interaction mutually exclusive with that of PR65/A. Tap42/alpha4 is also an interacting subunit of the PP2Ac-related phosphatases, PP4 and PP6. Tap42/alpha4, an essential protein in yeast and suppressor of apoptosis in mammals, contributes to critical cellular functions including the Tor signaling pathway. Here, we describe the crystal structure of the PP2Ac-interaction domain of Saccharomyces cerevisiae Tap42. The structure reveals an all alpha-helical protein with striking similarity to 14-3-3 and tetratricopeptide repeat (TPR) proteins. Mutational analyses of structurally conserved regions of Tap42/alpha4 identified a positively charged region critical for its interactions with PP2Ac. We propose a scaffolding function for Tap42/alpha4 whereby the interaction of PP2Ac at its N-terminus promotes the dephosphorylation of substrates recruited to the C-terminal region of the molecule.
蛋白磷酸酶2A（PP2A）的生理功能是通过其催化亚基（PP2Ac）与多种调节亚基的结合来确定的。PP2Ac的主要形式组装成一个异源三聚体，包括支架PR65/A亚基和一个可变的调节B亚基。一种不同的PP2Ac群体与Tap42/alpha4亚基结合，这种相互作用与PR65/A的相互作用相互排斥。Tap42/alpha4也是与PP2Ac相关的磷酸酶PP4和PP6的相互作用亚基。Tap42/alpha4是酵母中的一种必需蛋白，也是哺乳动物细胞凋亡的抑制因子，它参与包括Tor信号通路在内的关键细胞功能。在这里，我们描述了酿酒酵母Tap42的PP2Ac相互作用结构域的晶体结构。该结构揭示了一种全α螺旋蛋白，与14-3-3和四肽重复（TPR）蛋白具有惊人的相似性。对Tap42/alpha4结构保守区域的突变分析确定了一个对其与PP2Ac相互作用至关重要的带正电区域。我们提出Tap42/alpha4具有支架功能，即PP2Ac在其N端的相互作用促进了招募到分子C端区域的底物的去磷酸化。
