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Open AccessArticle

PEA-15 C-Terminal Tail Allosterically Modulates Death-Effector Domain Conformation and Facilitates Protein–Protein Interactions

Department of Chemistry, New Jersey City University, Jersey City, NJ 07305-1596, USA
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Int. J. Mol. Sci. 2019, 20(13), 3335; https://doi.org/10.3390/ijms20133335
Received: 5 June 2019 / Revised: 28 June 2019 / Accepted: 5 July 2019 / Published: 7 July 2019
(This article belongs to the Special Issue Protein Structural Dynamics 2019)
Phosphoprotein enriched in astrocytes, 15 kDa (PEA-15) exerts its regulatory roles on several critical cellular pathways through protein–protein interactions depending on its phosphorylation states. It can either inhibit the extracellular signal-regulated kinase (ERK) activities when it is dephosphorylated or block the assembly of death-inducing signaling complex (DISC) and the subsequent activation of apoptotic initiator, caspase-8, when it is phosphorylated. Due to the important roles of PEA-15 in regulating these pathways that lead to opposite cellular outcomes (cell proliferation vs. cell death), we proposed a phosphostasis (phosphorylation homeostasis) model, in which the phosphorylation states of the protein are vigorously controlled and regulated to maintain a delicate balance. The phosphostasis gives rise to the protective cellular functions of PEA-15 to preserve optimum cellular conditions. In this article, using advanced multidimensional nuclear magnetic resonance (NMR) techniques combined with a novel chemical shift (CS)-Rosetta algorithm for de novo protein structural determination, we report a novel conformation of PEA-15 death-effector domain (DED) upon interacting with ERK2. This new conformation is modulated by the irregularly structured C-terminal tail when it first recognizes and binds to ERK2 at the d-peptide recruitment site (DRS) in an allosteric manner, and is facilitated by the rearrangement of the surface electrostatic and hydrogen-bonding interactions on the DED. In this ERK2-bound conformation, three of the six helices (α2, α3, and α4) comprising the DED reorient substantially in comparison to the free-form structure, exposing key residues on the other three helices that directly interact with ERK2 at the DEF-docking site (docking site for ERK, FxF) and the activation loop. Additionally, we provide evidence that the phosphorylation of the C-terminal tail leads to a distinct conformation of DED, allowing efficient interactions with Fas-associated death domain (FADD) protein at the DISC. Our results substantiate the allosteric regulatory roles of the C-terminal tail in modulating DED conformation and facilitating protein–protein interactions of PEA-15. View Full-Text
Keywords: protein–protein interaction; mitogen-activated protein (MAP) kinase; apoptosis; protein structure; nuclear magnetic resonance (NMR) protein–protein interaction; mitogen-activated protein (MAP) kinase; apoptosis; protein structure; nuclear magnetic resonance (NMR)
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Crespo-Flores, S.L.; Cabezas, A.; Hassan, S.; Wei, Y. PEA-15 C-Terminal Tail Allosterically Modulates Death-Effector Domain Conformation and Facilitates Protein–Protein Interactions. Int. J. Mol. Sci. 2019, 20, 3335.

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