6P6C

CS-Rosetta Model of PEA-15 Death Effector Domain in the Complex with ERK2

Summary for 6P6C

• Entry DOI: 10.2210/pdb6p6c/pdb
• NMR Information: BMRB: 30614
• Descriptor: Astrocytic phosphoprotein PEA-15 (1 entity in total)
• Functional Keywords: protein-protein interaction, map kinase, apoptosis
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 15061.08

Authors

Wei, Y.,Crespo Flores, S.,Cabezas, A.,Hassan, S. (deposition date: 2019-06-03, release date: 2019-07-24, Last modification date: 2024-05-15)

Primary citation

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, 20:-, 2019

PubMed Abstract: 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.

PubMed: 31284641
DOI: 10.3390/ijms20133335

Experimental method

SOLUTION NMR