Department of Chemistry, New Jersey City University, Jersey City, NJ, 07305, USA.
Ministry of Natural Resources, Third Institute of Oceanography, Xiamen, 361005, Fujian, China.
Sci Rep. 2022 Jan 7;12(1):116. doi: 10.1038/s41598-021-04099-6.
Phosphoprotein enriched in astrocytes, 15 kDa (PEA-15) is a death-effector domain (DED) containing protein involved in regulating mitogen-activated protein kinase and apoptosis pathways. In this molecular dynamics study, we examined how phosphorylation of the PEA-15 C-terminal tail residues, Ser-104 and Ser-116, allosterically mediates conformational changes of the DED and alters the binding specificity from extracellular-regulated kinase (ERK) to Fas-associated death domain (FADD) protein. We delineated that the binding interfaces between the unphosphorylated PEA-15 and ERK2 and between the doubly phosphorylated PEA-15 and FADD are similarly composed of a scaffold that includes both the DED and the C-terminal tail residues of PEA-15. While the unphosphorylated serine residues do not directly interact with ERK2, the phosphorylated Ser-116 engages in strong electrostatic interactions with arginine residues on FADD DED. Upon PEA-15 binding, FADD repositions its death domain (DD) relative to the DED, an essential conformational change to allow the death-inducing signaling complex (DISC) assembly.
富含星形胶质细胞的磷酸化蛋白 15kDa（PEA-15）是一种死亡效应结构域（DED）包含蛋白，参与调节丝裂原活化蛋白激酶和细胞凋亡途径。在这项分子动力学研究中，我们研究了 PEA-15 C 末端尾部残基丝氨酸 104 和丝氨酸 116 的磷酸化如何变构调节 DED 的构象变化，并改变结合特异性，从细胞外调节激酶（ERK）到 Fas 相关死亡结构域（FADD）蛋白。我们描述了未磷酸化 PEA-15 和 ERK2 之间以及双磷酸化 PEA-15 和 FADD 之间的结合界面相似，都由一个支架组成，包括 DED 和 PEA-15 的 C 末端尾部残基。虽然未磷酸化的丝氨酸残基不直接与 ERK2 相互作用，但磷酸化的丝氨酸 116 与 FADD DED 上的精氨酸残基发生强烈的静电相互作用。PEA-15 结合后，FADD 将其死亡结构域（DD）相对于 DED 重新定位，这是允许死亡诱导信号复合物（DISC）组装的必要构象变化。
