Solution structure of ERK2 binding domain of MAPK phosphatase MKP-3: structural insights into MKP-3 activation by ERK2.
MAP kinases (MAPKs), which control mitogenic signal transduction in all eukaryotic organisms, are inactivated by dual specificity MAPK phosphatases (MKPs). MKP-3, a prototypical MKP, achieves substrate specificity through its N-terminal domain binding to the MAPK ERK2, resulting in the activation of its C-terminal phosphatase domain. The solution structure and biochemical analysis of the ERK2 binding (EB) domain of MKP-3 show that regions that are essential for ERK2 binding partly overlap with its sites that interact with the C-terminal catalytic domain, and that these interactions are functionally coupled to the active site residues of MKP-3. Our findings suggest a novel mechanism by which the EB domain binding to ERK2 is transduced to cause a conformational change of the C-terminal catalytic domain, resulting in the enzymatic activation of MKP-3.
Structural Biology Program, Department of Physiology and Biophysics, Mount Sinai School of Medicine, New York University, New York, NY 10029, USA.
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Farooq
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Chaturvedi
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Mujtaba
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Plotnikova
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Zeng
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Dhalluin
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Ashton
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Zhou
D000595:Amino Acid Sequence; D001665:Binding Sites; D015153:Blotting, Western; D020134:Catalytic Domain; D054642:Dual Specificity Phosphatase 6; D004789:Enzyme Activation; D006801:Humans; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D008954:Models, Biological; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016296:Mutagenesis; D019906:Nuclear Magnetic Resonance, Biomolecular; D011485:Protein Binding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D017027:Protein Tyrosine Phosphatases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D016415:Sequence Alignment; D055672:Static Electricity
D011993:Recombinant Fusion Proteins; D019950:Mitogen-Activated Protein Kinase 1; C517035:DUSP6 protein, human; D054642:Dual Specificity Phosphatase 6; D017027:Protein Tyrosine Phosphatases