Substantial conformational change mediated by charge-triad residues of the death effector domain in protein-protein interactions

PLoS One. 2013 Dec 31;8(12):e83421. doi: 10.1371/journal.pone.0083421. eCollection 2013.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis Regulatory Proteins
  • Death Domain Receptor Signaling Adaptor Proteins / chemistry*
  • Death Domain Receptor Signaling Adaptor Proteins / metabolism
  • Hydrogen Bonding
  • Mice
  • Mitogen-Activated Protein Kinase 1 / chemistry
  • Mitogen-Activated Protein Kinase 1 / metabolism
  • Models, Molecular
  • Nuclear Magnetic Resonance, Biomolecular
  • Phosphoproteins / chemistry*
  • Phosphoproteins / metabolism
  • Protein Interaction Domains and Motifs*
  • Protein Structure, Secondary
  • Static Electricity

Substances

  • Apoptosis Regulatory Proteins
  • Death Domain Receptor Signaling Adaptor Proteins
  • Dedd protein, mouse
  • Pea15 protein, mouse
  • Phosphoproteins
  • Mitogen-Activated Protein Kinase 1