Juyoux, Pauline;
Galdadas, Ioannis;
Gobbo, Dorothea;
von Velsen, Jill;
Pelosse, Martin;
Tully, Mark;
Vadas, Oscar;
... Bowler, Matthew W; + view all
(2023)
Architecture of the MKK6-p38α complex defines the basis of MAPK specificity and activation.
Science
, 381
(6663)
pp. 1217-1225.
10.1126/science.add7859.
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Abstract
The mitogen-activated protein kinase (MAPK) p38α is a central component of signaling in inflammation and the immune response and is, therefore, an important drug target. Little is known about the molecular mechanism of its activation by double phosphorylation from MAPK kinases (MAP2Ks), because of the challenge of trapping a transient and dynamic heterokinase complex. We applied a multidisciplinary approach to generate a structural model of p38α in complex with its MAP2K, MKK6, and to understand the activation mechanism. Integrating cryo-electron microscopy with molecular dynamics simulations, hydrogen-deuterium exchange mass spectrometry, and experiments in cells, we demonstrate a dynamic, multistep phosphorylation mechanism, identify catalytically relevant interactions, and show that MAP2K-disordered amino termini determine pathway specificity. Our work captures a fundamental step of cell signaling: a kinase phosphorylating its downstream target kinase.
| Type: | Article |
|---|---|
| Title: | Architecture of the MKK6-p38α complex defines the basis of MAPK specificity and activation |
| Location: | United States |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1126/science.add7859 |
| Publisher version: | https://doi.org/10.1126/science.add7859 |
| Language: | English |
| Additional information: | This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions. |
| Keywords: | Cryoelectron Microscopy, Enzyme Activation, MAP Kinase Kinase 2, MAP Kinase Kinase 6, Mitogen-Activated Protein Kinase 14, Phosphorylation, Substrate Specificity, Protein Conformation |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > UCL BEAMS UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Maths and Physical Sciences UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Maths and Physical Sciences > Dept of Chemistry |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10180326 |
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