title: Profound conformational changes of PED/PEA-15 in ERK2 complex revealed by NMR backbone dynamics.
abstract: PED/PEA-15 is a small, non-catalytic, DED containing protein that is widely expressed in different tissues and highly conserved among mammals. PED/PEA-15 has been found to interact with several protein targets in various pathways, including FADD and procaspase-8 (apoptosis), ERK1/2 (cell cycle entry), and PLD1/2 (diabetes). In this research, we have studied the PED/PEA-15 in a complex with ERK2, a MAP kinase, using NMR spectroscopic techniques. MAP Kinase signaling pathways are involved in the regulation of many cellular functions, including cell proliferation, differentiation, apoptosis and survival. ERK1/2 are activated by a variety of external stimuli, including growth factors, hormones and neurotransmitters. Inactivated ERK2 is primarily found in the cytosol. Once the ERK/MAPK cascade is initiated, ERK2 is phosphorylated and stimulated, allowing it to redistribute in the cell nucleus and act as a transcription factor. Previous studies have shown that PED/PEA-15 complexes with ERK2 in the cytoplasm and prevents redistribution into the nucleus. Although the NMR structure and dynamics of PED/PEA-15 in the free form have been documented recently, no detailed structural and dynamic information for the ERK2-bound form is available. Here we report NMR chemical shift perturbation and backbone dynamic studies at the fast ps-ns timescale of PED/PEA-15, in its free form and in the complex with ERK2. These analyses characterize motions and conformational changes involved in ERK2 recognition and binding that orchestrate the reorganization of the DED and immobilization of the C-terminal tail. A new induced fit binding model for PED/PEA-15 is proposed.
authors: Department of Chemistry and Biochemistry, Seton Hall University, South Orange, NJ 07079, USA.
authors: Edward C
authors: EC
authors: Twomey
authors: Dana F
authors: DF
authors: Cordasco
authors: Yufeng
authors: Y
authors: Wei
mesh_terms: D000595:Amino Acid Sequence; D051017:Apoptosis Regulatory Proteins; D047908:Intracellular Signaling Peptides and Proteins / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy / Q000379:methods*; D019950:Mitogen-Activated Protein Kinase 1 / Q000737:chemistry*; D008969:Molecular Sequence Data; D010750:Phosphoproteins / Q000737:chemistry*; D011487:Protein Conformation
chemical_list: D051017:Apoptosis Regulatory Proteins; D047908:Intracellular Signaling Peptides and Proteins; C092039:PEA15 protein, human; D010750:Phosphoproteins; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1