5O90

Crystal structure of a P38alpha T185G mutant in complex with TAB1 peptide.

Summary for 5O90

• Entry DOI: 10.2210/pdb5o90/pdb
• Descriptor: Mitogen-activated protein kinase 14, TGF-beta-activated kinase 1 and MAP3K7-binding protein 1, 4-(4-FLUOROPHENYL)-1-(4-PIPERIDINYL)-5-(2-AMINO-4-PYRIMIDINYL)-IMIDAZOLE, ... (4 entities in total)
• Functional Keywords: mapk14 transferase tab1, transferase
• Biological source: Mus musculus (Mouse); More
• Cellular location: Cytoplasm : P47811
• Total number of polymer chains: 2
• Total formula weight: 44735.01

Authors

Nichols, C.E.,De Nicola, G.F.,Thapa, D. (deposition date: 2017-06-15, release date: 2018-01-31, Last modification date: 2024-01-17)

Primary citation

Thapa, D.,Nichols, C.,Bassi, R.,Martin, E.D.,Verma, S.,Conte, M.R.,De Santis, V.,De Nicola, G.F.,Marber, M.S.
TAB1-Induced Autoactivation of p38 alpha Mitogen-Activated Protein Kinase Is Crucially Dependent on Threonine 185.
Mol. Cell. Biol., 38:-, 2018

PubMed Abstract: p38α mitogen-activated protein kinase is essential to cellular homeostasis. Two principal mechanisms to activate p38α exist. The first relies on dedicated dual-specificity kinases such as mitogen-activated protein kinase kinase (MAP2K) 3 (MKK3) or 6 (MKK6), which activate p38α by phosphorylating Thr180 and Tyr182 within the activation segment. The second is by autophosphorylation of Thr180 and Tyr182 in , mediated by p38α binding the scaffold protein TAB1. The second mechanism occurs during myocardial ischemia, where it aggravates myocardial infarction. Based on the crystal structure of the p38α-TAB1 complex we replaced threonine 185 of p38α with glycine (T185G) to prevent an intramolecular hydrogen bond with Asp150 from being formed. This mutation did not interfere with TAB1 binding to p38α. However, it disrupted the consequent long-range effect of this binding event on the distal activation segment, releasing the constraint on Thr180 that oriented its hydroxyl for phosphotransfer. Based on assays performed and , the autoactivation of p38α(T185G) was disabled, while its ability to be activated by upstream MAP2Ks and to phosphorylate downstream substrates remained intact. Furthermore, myocardial cells expressing p38α(T185G) were resistant to injury. These findings reveal a mechanism to selectively disable p38α autoactivation and its consequences, which may ultimately circumvent the toxicity associated with strategies that inhibit p38α kinase activity under all circumstances, such as with ATP-competitive inhibitors.

PubMed: 29229647
DOI: 10.1128/MCB.00409-17

Experimental method

X-RAY DIFFRACTION (2.49 Å)