title: Substantial conformational change mediated by charge-triad residues of the death effector domain in protein-protein interactions.
abstract: Protein conformational changes are commonly associated with the formation of protein complexes. The non-catalytic death effector domains (DEDs) mediate protein-protein interactions in a variety of cellular processes, including apoptosis, proliferation and migration, and glucose metabolism. Here, using NMR residual dipolar coupling (RDC) data, we report a conformational change in the DED of the phosphoprotein enriched in astrocytes, 15 kDa (PEA-15) protein in the complex with a mitogen-activated protein (MAP) kinase, extracellular regulated kinase 2 (ERK2), which is essential in regulating ERK2 cellular distribution and function in cell proliferation and migration. The most significant conformational change in PEA-15 happens at helices α2, α3, and α4, which also possess the highest flexibility among the six-helix bundle of the DED. This crucial conformational change is modulated by the D/E-RxDL charge-triad motif, one of the prominent structural features of DEDs, together with a number of other electrostatic and hydrogen bonding interactions on the protein surface. Charge-triad motif promotes the optimal orientation of key residues and expands the binding interface to accommodate protein-protein interactions. However, the charge-triad residues are not directly involved in the binding interface between PEA-15 and ERK2.
authors.affiliation: Institute of NeuroImmune Pharmacology, Seton Hall University, South Orange, New Jersey, United States of America ; Department of Chemistry and Biochemistry, Seton Hall University, South Orange, New Jersey, United States of America ; Integrated Program in Cellular, Molecular, and Biomedical Studies, Columbia University, New York, New York, United States of America.
authors.forename: Edward C
authors.initials: EC
authors.lastname: Twomey
authors.affiliation: Institute of NeuroImmune Pharmacology, Seton Hall University, South Orange, New Jersey, United States of America ; Department of Chemistry and Biochemistry, Seton Hall University, South Orange, New Jersey, United States of America.
authors.forename: Dana F
authors.initials: DF
authors.lastname: Cordasco
authors.affiliation: Department of Chemistry and Biochemistry, Seton Hall University, South Orange, New Jersey, United States of America.
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Kozuch
authors.affiliation: Institute of NeuroImmune Pharmacology, Seton Hall University, South Orange, New Jersey, United States of America.
authors.forename: Yufeng
authors.initials: Y
authors.lastname: Wei
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins; D053418:Death Domain Receptor Signaling Adaptor Proteins / Q000737:chemistry* / Q000378:metabolism; D006860:Hydrogen Bonding; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000737:chemistry / Q000378:metabolism; D008958:Models, Molecular; D019906:Nuclear Magnetic Resonance, Biomolecular; D010750:Phosphoproteins / Q000737:chemistry* / Q000378:metabolism; D054730:Protein Interaction Domains and Motifs; D017433:Protein Structure, Secondary; D055672:Static Electricity
chemical_list: D051017:Apoptosis Regulatory Proteins; D053418:Death Domain Receptor Signaling Adaptor Proteins; C486432:Dedd protein, mouse; C490444:Pea15 protein, mouse; D010750:Phosphoproteins; D019950:Mitogen-Activated Protein Kinase 1