Kinase Activation by Small Conformational Changes
- Elias D. LopezElias D. LopezDepartamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Ciudad Autónoma de Buenos Aires, ArgentinaMore by Elias D. Lopez
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- Osvaldo BurasteroOsvaldo BurasteroDepartamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Ciudad Autónoma de Buenos Aires, ArgentinaMore by Osvaldo Burastero
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- Juan P. ArconJuan P. ArconDepartamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Ciudad Autónoma de Buenos Aires, ArgentinaMore by Juan P. Arcon
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- Lucas A. DefelipeLucas A. DefelipeDepartamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Ciudad Autónoma de Buenos Aires, ArgentinaMore by Lucas A. Defelipe
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- Natalie G. AhnNatalie G. AhnDepartment of Chemistry and Biochemistry, University of Colorado, Boulder, Colorado 80309, United StatesMore by Natalie G. Ahn
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- Marcelo A. MartiMarcelo A. MartiDepartamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Ciudad Autónoma de Buenos Aires, ArgentinaMore by Marcelo A. Marti
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- Adrian G. Turjanski*Adrian G. TurjanskiE-mail: [email protected]Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Ciudad Autónoma de Buenos Aires, ArgentinaMore by Adrian G. Turjanski
Abstract
Protein kinases (PKs) are allosteric enzymes that play an essential role in signal transduction by regulating a variety of key cellular processes. Most PKs suffer conformational rearrangements upon phosphorylation that strongly enhance the catalytic activity. Generally, it involves the movement of the phosphorylated loop toward the active site and the rotation of the whole C-terminal lobe. However, not all kinases undergo such a large configurational change: The MAPK extracellular signal-regulated protein kinases ERK1 and ERK2 achieve a 50 000 fold increase in kinase activity with only a small motion of the C-terminal region. In the present work, we used a combination of molecular simulation tools to characterize the conformational landscape of ERK2 in the active (phosphorylated) and inactive (unphosphorylated) states in solution in agreement with NMR experiments. We show that the chemical reaction barrier is strongly dependent on ATP conformation and that the “active” low-barrier configuration is subtly regulated by phosphorylation, which stabilizes a key salt bridge between the conserved Lys52 and Glu69 belonging to helix-C and promotes binding of a second Mg ion. Our study highlights that the on–off switch embedded in the kinase fold can be regulated by small, medium, and large conformational changes.
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