Recognition of ERK MAP kinase by PEA-15 reveals a common docking site within the death domain and death effector domain

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Abstract
PEA‐15 is a multifunctional protein that modulates signaling pathways which control cell proliferation and cell death. In particular, PEA‐15 regulates the actions of the ERK MAP kinase cascade by binding to ERK and altering its subcellular localization. The three‐dimensional structure of PEA‐15 has been determined using NMR spectroscopy and its interaction with ERK defined by characterization of mutants that modulate ERK function. PEA‐15 is composed of an N‐terminal death effector domain (DED) and a C‐terminal tail of irregular structure. NMR ‘footprinting’ and mutagenesis identified elements of both the DED and tail that are required for ERK binding. Comparison of the DED‐binding surface for ERK2 with the death domain (DD)‐binding surface of Drosophila Tube revealed an unexpected similarity between the interaction modes of the DD and DED motifs in these proteins. Despite a lack of functional or sequence similarity between PEA‐15 and Tube, these proteins utilize a common surface of the structurally similar DD and DED to recognize functionally diverse targets.