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Originally published In Press as doi:10.1074/jbc.C200418200 on August 8, 2002

J. Biol. Chem., Vol. 277, Issue 40, 37401-37405, October 4, 2002
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Structure of Mitogen-activated Protein Kinase-activated Protein (MAPKAP) Kinase 2 Suggests a Bifunctional Switch That Couples Kinase Activation with Nuclear Export*

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

From Vertex Pharmaceuticals Inc., Cambridge, Massachusetts 02139

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.

* The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The atomic coordinates and the structure factors (code 1KWP) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

Dagger To whom correspondence should be addressed: Vertex Pharmaceuticals Inc., 130 Waverly St., Cambridge, MA 02139. Tel.: 617-444-6471; Fax: 617-444-6688; E-mail: wuyi_meng@vpharm.com.

Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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