An Allosteric Cross-Talk Between the Activation Loop and the ATP Binding Site Regulates the Activation of Src Kinase

Phosphorylation of the activation loop is a fundamental step in the activation of most protein kinases. In the case of the Src tyrosine kinase, a prototypical kinase due to its role in cancer and its historic importance, phosphorylation of tyrosine 416 in the activation loop is known to rigidify the...

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Bibliographic Details
Published in:Scientific reports 2016-04, Vol.6 (1), p.24235-24235, Article 24235
Main Authors: Pucheta-Martínez, Encarna, Saladino, Giorgio, Morando, Maria Agnese, Martinez-Torrecuadrada, Jorge, Lelli, Moreno, Sutto, Ludovico, D'Amelio, Nicola, Gervasio, Francesco Luigi
Format: Article
Language:English
Subjects:
Adenosine Triphosphate - metabolism
Allosteric properties
Allosteric Regulation
Binding Sites
Cancer
Catalytic Domain
Humans
Kinases
Molecular Dynamics Simulation
Nuclear Magnetic Resonance, Biomolecular
Phosphorylation
Protein-tyrosine kinase
Src protein
src-Family Kinases - chemistry
src-Family Kinases - metabolism
Thermodynamics
Tyrosine - metabolism
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Summary:Phosphorylation of the activation loop is a fundamental step in the activation of most protein kinases. In the case of the Src tyrosine kinase, a prototypical kinase due to its role in cancer and its historic importance, phosphorylation of tyrosine 416 in the activation loop is known to rigidify the structure and contribute to the switch from the inactive to a fully active form. However, whether or not phosphorylation is able per-se to induce a fully active conformation, that efficiently binds ATP and phosphorylates the substrate, is less clear. Here we employ a combination of solution NMR and enhanced-sampling molecular dynamics simulations to fully map the effects of phosphorylation and ATP/ADP cofactor loading on the conformational landscape of Src tyrosine kinase. We find that both phosphorylation and cofactor binding are needed to induce a fully active conformation. What is more, we find a complex interplay between the A-loop and the hinge motion where the phosphorylation of the activation-loop has a significant allosteric effect on the dynamics of the C-lobe.
ISSN:2045-2322
2045-2322
DOI:10.1038/srep24235