期刊
NATURE STRUCTURAL & MOLECULAR BIOLOGY
卷 21, 期 8, 页码 704-711出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/nsmb.2861
关键词
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资金
- Japan New Energy and Industrial Technology Development Organization (NEDO)
- Japanese Ministry of Education, Culture, Sports, Science and Technology (MEXT) [25121743]
- Japan Society for the Promotion of Science (JSPS)
- Grants-in-Aid for Scientific Research [26102735, 21121001] Funding Source: KAKEN
Mitogen-activated protein kinases (MAPKs) are essential to intracellular signal transduction. MAPKs anchor their pathway-specific substrates through so-called 'docking interactions' at locations distal from the active site. Docking interactions ensure efficient substrate recognition, but their contribution to the kinase reaction itself remains unclear. Herein, we use solution NMR to analyze the interaction between dually phosphorylated, active human p38 alpha and the C-terminal fragments of its substrate MK2. p38 alpha phosphorylation and ATP loading collaboratively induce the active conformation; subsequently, p38 alpha accommodates MK2 phosphoacceptor residues in its active site. The docking interaction enhances binding of ATP and the phosphoacceptor to p38 alpha, accelerating the phosphotransfer reaction. Thus, the docking interaction enhances p38 alpha's enzymatic activity toward pathway-specific substrates allosterically as well as by the anchor effect. These findings clarify how MAPK cascades are organized in cells, even under ATP-depleted conditions often associated with environmental stress.
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