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

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 co...

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Autores principales: Cho, Yong-Soon, Yoo, Jiho, Park, Soomin, Cho, Hyun-Soo
Formato: Online Artículo Texto
Lenguaje:English
Publicado: International Union of Crystallography 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3940201/
https://www.ncbi.nlm.nih.gov/pubmed/24531485
http://dx.doi.org/10.1107/S1399004713027806
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author Cho, Yong-Soon
Yoo, Jiho
Park, Soomin
Cho, Hyun-Soo
author_facet Cho, Yong-Soon
Yoo, Jiho
Park, Soomin
Cho, Hyun-Soo
author_sort Cho, Yong-Soon
collection PubMed
description 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.
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spelling pubmed-39402012014-03-04 The structures of the kinase domain and UBA domain of MPK38 suggest the activation mechanism for kinase activity Cho, Yong-Soon Yoo, Jiho Park, Soomin Cho, Hyun-Soo Acta Crystallogr D Biol Crystallogr Research Papers 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. International Union of Crystallography 2014-01-31 /pmc/articles/PMC3940201/ /pubmed/24531485 http://dx.doi.org/10.1107/S1399004713027806 Text en © Cho et al. 2014 http://creativecommons.org/licenses/by/2.0/uk/ This is an open-access article distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original authors and source are cited.
spellingShingle Research Papers
Cho, Yong-Soon
Yoo, Jiho
Park, Soomin
Cho, Hyun-Soo
The structures of the kinase domain and UBA domain of MPK38 suggest the activation mechanism for kinase activity
title The structures of the kinase domain and UBA domain of MPK38 suggest the activation mechanism for kinase activity
title_full The structures of the kinase domain and UBA domain of MPK38 suggest the activation mechanism for kinase activity
title_fullStr The structures of the kinase domain and UBA domain of MPK38 suggest the activation mechanism for kinase activity
title_full_unstemmed The structures of the kinase domain and UBA domain of MPK38 suggest the activation mechanism for kinase activity
title_short The structures of the kinase domain and UBA domain of MPK38 suggest the activation mechanism for kinase activity
title_sort structures of the kinase domain and uba domain of mpk38 suggest the activation mechanism for kinase activity
topic Research Papers
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3940201/
https://www.ncbi.nlm.nih.gov/pubmed/24531485
http://dx.doi.org/10.1107/S1399004713027806
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