Related Experiment Videos
Structure of mitogen-activated protein kinase-activated protein (MAPKAP) kinase 2 suggests a bifunctional switch that
Wuyi Meng1, Lora L Swenson, Matthew J Fitzgibbon
1Vertex Pharmaceuticals Inc., Cambridge, Massachusetts 02139, USA. wuyi_meng@vpharm.com
Abstract:
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 A 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.
Insights
MAPK-activated protein kinase 2 (MAPKAPK2) is crucial for inflammation. Its structure reveals an inactive conformation, with phosphorylation controlling nuclear transport via p38 MAPK binding.
Area of Science:
- Biochemistry
- Molecular Biology
- Structural Biology
Background:
- MAPK-activated protein kinase 2 (MAPKAPK2) is activated by p38 MAPK and mediates inflammatory responses.
- MAPKAPK2 phosphorylates diverse nuclear and cytoplasmic targets, regulating cellular functions.
Purpose of the Study:
- To determine the crystal structure of unphosphorylated MAPKAPK2.
- To elucidate the structural basis for MAPKAPK2 activity and regulation.
Main Methods:
- X-ray crystallography at 2.8 A resolution.
- Structural analysis of the kinase and C-terminal regulatory domains.
Main Results:
- The crystal structure of unphosphorylated MAPKAPK2 revealed an inactive protein with the kinase domain in an active conformation.
- Aspartate 366 mimics the activating phosphorylation at threonine 222.
- Phosphorylation at threonine 334 acts as a switch for nuclear import/export by modulating p38 binding and exposing nuclear export signals.
Conclusions:
- The structure provides insights into MAPKAPK2 regulation and its role in inflammatory signaling.
- Phosphorylation-dependent interactions with p38 MAPK govern MAPKAPK2 subcellular localization.