NMR backbone dynamics studies of human PED/PEA-15 outline protein functional sites

PEDPEA-15 (phosphoprotein enriched in diabetesphosphoprotein enriched in astrocytes) is a ubiquitously expressed protein and a key regulator of cell growth and glucose metabolism. PEDPEA-15 mediates both homotypic and heterotypic interactions and is constituted by an N-terminal canonical death effector domain and a C-terminal tail. In the present study, the backbone dynamics of PEDPEA-15 via 15N R1 and R2 and steady-state [1H]-15N NOE measurements is reported. The dynamic parameters were analyzed using both Lipari-Szabo model-free formalism and a reduced spectral density mapping approach. The results obtained define a polar and charged surface of the death effector domain characterized by internal motions in the micro- to millisecond timescale, which is crucial for the multiple heterotypic functional protein-protein interactions in which PEDPEA-15 is involved. The present study contributes to a better understanding of the molecular basis of the PEDPEA-15 functional interactions and provides a more detailed surface for the design and development of PEDPEA-15 binders. © 2010 FEBS.