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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...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
International Union of Crystallography
2014
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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. |
format | Online Article Text |
id | pubmed-3940201 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | International Union of Crystallography |
record_format | MEDLINE/PubMed |
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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