ArticleJournal of molecular biology2012
A conserved Glu-Arg salt bridge connects coevolved motifs that define the eukaryotic protein kinase fold.
Article in Journal of molecular biology, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers.
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26 citing papers in PubMed, 44 citations in OpenAlex.
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- Calculation of centralities in protein kinase A.Proceedings of the National Academy of Sciences of the United States of America · 2022Article
- Differential maturation and chaperone dependence of the paralogous protein kinases DYRK1A and DYRK1B.Scientific reports · 2022Article
- Direct phosphorylation of HY5 by SPA kinases to regulate photomorphogenesis in Arabidopsis.The New phytologist · 2021Article
- Novel method to identify group-specific non-catalytic pockets of human kinome for drug design.RSC advances · 2020Article
- A phyB-PIF1-SPA1 kinase regulatory complex promotes photomorphogenesis in Arabidopsis.Nature communications · 2019Article
- Zooming in on protons: Neutron structure of protein kinase A trapped in a product complex.Science advances · 2019Article
- The dimer-dependent catalytic activity of RAF family kinases is revealed through characterizing their oncogenic mutants.Oncogene · 2018Article
- Functional characterization of DYRK1A missense variants associated with a syndromic form of intellectual deficiency and autism.Biology open · 2018Article
- Structural characterization of the catalytic γ and regulatory β subunits of phosphorylase kinase in the context of the hexadecameric enzyme complex.Protein science : a publication of the Protein Society · 2018Article
- Structures of the inactive and active states of RIP2 kinase inform on the mechanism of activation.PloS one · 2017Article
- Dynamics-Driven Allostery in Protein Kinases.Trends in biochemical sciences · 2015Review
- Integration of signaling in the kinome: Architecture and regulation of the αC Helix.Biochimica et biophysica acta · 2015Article
- The Tribbles 2 (TRB2) pseudokinase binds to ATP and autophosphorylates in a metal-independent manner.The Biochemical journal · 2015Article
- Global connectivity of hub residues in Oncoprotein structures encodes genetic factors dictating personalized drug response to targeted Cancer therapy.Scientific reports · 2014Article
- Dynamic architecture of a protein kinase.Proceedings of the National Academy of Sciences of the United States of America · 2014Article
- Structure of cyclin G-associated kinase (GAK) trapped in different conformations using nanobodies.The Biochemical journal · 2014Article
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9 authors at 3 institutions in 1 country.
Funding
Abstract
Eukaryotic protein kinases (EPKs) feature two coevolved structural segments, the Activation segment, which starts with the Asp-Phe-Gly (DFG) and ends with the Ala-Pro-Glu (APE) motifs, and the helical GHI subdomain that comprises αG-αH-αI helices. Eukaryotic-like kinases have a much shorter Activation segment and lack the GHI subdomain. They thus lack the conserved salt bridge interaction between the APE Glu and an Arg from the GHI subdomain, a hallmark signature of EPKs. Although the conservation of this salt bridge in EPKs is well known and its implication in diseases has been illustrated by polymorphism analysis, its function has not been carefully studied. In this work, we use murine cAMP-dependent protein kinase (protein kinase A) as the model enzyme (Glu208 and Arg280) to examine the role of these two residues. We showed that Ala replacement of either residue caused a 40- to 120-fold decrease in catalytic efficiency of the enzyme due to an increase in K(m)(ATP) and a decrease in k(cat). Crystal structures, as well as solution studies, also demonstrate that this ion pair contributes to the hydrophobic network and stability of the enzyme. We show that mutation of either Glu or Arg to Ala renders both mutant proteins less effective substrates for upstream kinase phosphoinositide-dependent kinase 1. We propose that the Glu208-Arg280 pair serves as a center hub of connectivity between these two structurally conserved elements in EPKs. Mutations of either residue disrupt communication not only between the two segments but also within the rest of the molecule, leading to altered catalytic activity and enzyme regulation.
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