Structure of Mitogen-activated Protein Kinase-activated Protein (MAPKAP) Kinase 2 Suggests a Bifunctional Switch That Couples Kinase Activation with Nuclear Export

• Published in: The Journal of biological chemistry Vol. 277; no. 40; pp. 37401 - 37405
• Main Authors: Meng, Wuyi, Swenson, Lora L., Fitzgibbon, Matthew J., Hayakawa, Koto, ter Haar, Ernst, Behrens, Anne E., Fulghum, John R., Lippke, Judith A.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 04-10-2002; American Society for Biochemistry and Molecular Biology
• Subjects: Amino Acid Sequence; Cell Nucleus - metabolism; Cloning, Molecular; Enzyme Activation; Humans; Intracellular Signaling Peptides and Proteins; Models, Molecular; Molecular Sequence Data; Peptide Fragments - chemistry; Peptide Fragments - metabolism; Protein Structure, Secondary; Protein Transport; Protein-Serine-Threonine Kinases - chemistry; Protein-Serine-Threonine Kinases - metabolism; Recombinant Proteins - chemistry; Recombinant Proteins - metabolism; Sequence Alignment; Sequence Homology, Amino Acid
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.C200418200

MAPK-activated protein kinase 2 (MAPKAPK2), one of several kinases directly phosphorylated and activated by p38 MAPK, plays a central role in the inflammatory response. The activated MAPKAPK2 phosphorylates its nuclear targets CREB/ATF1, serum response factor, and E2A protein E47 and its cytoplasmic targets HSP25/27, LSP-1, 5-lipoxygenase, glycogen synthase, and tyrosine hydroxylase. The crystal structure of unphosphorylated MAPKAPK2, determined at 2.8 Å resolution, includes the kinase domain and the C-terminal regulatory domain. Although the protein is inactive, the kinase domain adopts an active conformation with aspartate 366 mimicking the missing phosphorylated threonine 222 in the activation loop. The C-terminal regulatory domain forms a helix-turn-helix plus a long strand. Phosphorylation of threonine 334, which is located between the kinase domain and the C-terminal regulatory domain, may serve as a switch for MAPKAPK2 nuclear import and export. Phosphorylated MAPKAPK2 masks the nuclear localization signal at its C terminus by binding to p38. It unmasks the nuclear export signal, which is part of the second C-terminal helix packed along the surface of kinase domain C-lobe, and thereby carries p38 to the cytoplasm.