title: The structures of the kinase domain and UBA domain of MPK38 suggest the activation mechanism for kinase activity.
abstract: Murine protein serine/threonine kinase 38 (MPK38) is the murine orthologue of human maternal embryonic leucine-zipper kinase (MELK), which belongs to the SNF1/AMPK family. MELK is considered to be a promising drug target for anticancer therapy because overexpression and hyperactivation of MELK is correlated with several human cancers. Activation of MPK38 requires the extended sequence (ExS) containing the ubiquitin-associated (UBA) linker and UBA domain and phosphorylation of the activation loop. However, the activation mechanism of MPK38 is unknown. This paper reports the crystal structure of MPK38 (T167E), which mimics a phosphorylated state of the activation loop, in complex with AMP-PNP. In the MPK38 structure, the UBA linker forces an inward movement of the αC helix. Phosphorylation of the activation loop then induces movement of the activation loop towards the C-lobe and results in interlobar cleft closure. These processes generate a fully active state of MPK38. This structure suggests that MPK38 has a similar molecular mechanism regulating activation as in other kinases of the SNF1/AMPK family.
authors: Department of Systems Biology, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749, Republic of Korea.
authors: Yong-Soon
authors: YS
authors: Cho
authors: Department of Systems Biology, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749, Republic of Korea.
authors: Jiho
authors: J
authors: Yoo
authors: Department of Systems Biology, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749, Republic of Korea.
authors: Soomin
authors: S
authors: Park
authors: Department of Systems Biology, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749, Republic of Korea.
authors: Hyun-Soo
authors: HS
authors: Cho
mesh_terms: D000266:Adenylyl Imidodiphosphate / Q000737:chemistry*; D000818:Animals; D018360:Crystallography, X-Ray; D004789:Enzyme Activation; D004926:Escherichia coli / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008958:Models, Molecular; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry* / Q000235:genetics; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics; D025801:Ubiquitin / Q000737:chemistry* / Q000235:genetics
chemical_list: D011994:Recombinant Proteins; D025801:Ubiquitin; D000266:Adenylyl Imidodiphosphate; C108524:Melk protein, mouse; D017346:Protein Serine-Threonine Kinases
keywords: MELK; MPK38; UBA linker; activation-loop phosphorylation; two-step activation model