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Structural Features of the Kinase Domain

  • Dániel Süveges
  • Natalia Jura
Chapter

Abstract

A fundamental role of receptor tyrosine kinases is to couple extracellular signals to tyrosine phosphorylation of cellular components. This reaction is carried out by an intracellular kinase domain, which becomes activated upon ligand binding to the receptor’s extracellular domain. The main substrates of the activated kinase are the phosphorylation sites located within the receptor. Those sites play two important roles—they regulate catalytic activity of the kinase and/or serve as docking sites that connect the receptors with high specificity to downstream effectors. The precise regulation of these phosphorylation events is therefore critical for receptor tyrosine kinase signaling and most frequently targeted by mutations in human diseases.

The most recognized and the best understood features that distinguish 58 receptor tyrosine kinases present in vertebrates are located within their extracellular ligand-binding domains, which share low or no homology between different receptor families. Another level of diversity is encoded by the flexible intracellular C-terminal tails, which contain different sets of tyrosine phosphorylation sites that couple receptors to unique effector repertoires. In contrast, the kinase domain is well conserved between different receptors. This is likely because the structural conservation within the catalytic domain is necessary to maintain its ability to catalyze phosphorylation. Surprisingly, the regulatory mechanisms that control catalysis differ significantly among receptors. These differences can be encoded by minor amino acid sequence changes in the kinase active site and/or allosteric modulation by the receptor regions that are adjacent to the kinase domain. This section reviews the currently understood structural features of the kinase domain and its activation mechanisms and their nuances operative in different receptor tyrosine kinase families.

Keywords

Epidermal Growth Factor Receptor Receptor Tyrosine Kinase Kinase Domain Activation Loop Inactive Conformation 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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© Springer Science+Business Media New York 2015

Authors and Affiliations

  1. 1.Department of Cellular and Molecular Pharmacology, Cardiovascular Research InstituteUniversity of California, San FranciscoSan FranciscoUSA
  2. 2.Department of Cellular and Molecular Pharmacology, Cardiovascular Research InstituteUniversity of California, San FranciscoSan FranciscoUSA

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