The structures of the kinase domain and UBA domain of MPK38 suggest the activation mechanism for kinase activity

Yong Soon Cho, Jiho Yoo, Soomin Park, Hyun Soo Cho

Research output: Contribution to journalArticle

7 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)514-521
Number of pages8
JournalActa Crystallographica Section D: Biological Crystallography
Volume70
Issue number2
DOIs
Publication statusPublished - 2014 Feb 1

All Science Journal Classification (ASJC) codes

  • Structural Biology

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