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C200418200v1
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Papers In Press, published online ahead of print August 8, 2002
J. Biol. Chem, 10.1074/jbc.C200418200
Submitted on July 22, 2002
Revised on August 6, 2002
Accepted on August 8, 2002

Structure of MAPKAP kinase 2 suggests a bifunctional switch that couples kinase ativation with nuclear export

Wuyi Meng, Lora L. Swenson, Matthew J. Fitzgibbon, Koto Hayakawa, Ernst ter Haar, Anne E. Behrens, John R. Fulghum, and Judith A. Lippke

X-ray, Vertex Pharmaceuticals Inc., Cambridge, MA 02139

Corresponding Author: wuyi_meng{at}vpharm.com

MAPKAP kinase 2, one of several kinases directly phosphorylated and activated by p38 MAP kinase, plays a central role in the inflammatory response. The activated MAPKAPK2 phosphorylates its nuclear targets CREB/ATF1, serum response factor, E2A protein E47 and its cytoplasmic targets HSP25/27, LSP-1, 5-lipoxygenase, glycogen synthase, 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.


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