Abstract
Autoregulatory Mechanisms in Protein-tyrosine Kinases
Highlights
The receptor tyrosine kinases (RTKs) family can be broadly divided into two groups depending on the covalent organization of the receptor
The vast majority of Protein-tyrosine kinases (PTKs) contain between one and three tyrosines in the kinase activation loop (A-loop), which comprises subdomains VII and VIII of the protein kinase catalytic core (4). Phosphorylation of these tyrosines has been shown to be critical for stimulation of catalytic activity and biological function for RTKs such as the insulin receptor (5), FGF receptor (6), hepatocyte growth factor receptor (MET) (7), and nerve growth factor receptor (TrkA) (8), and for non-receptor tyrosine kinases (NRTKs) such as Src (9), Zap-70 (10), and JAK2 (11)
Crystal structures of the unphosphorylated forms of the insulin receptor kinase domain (IRK) (14) and the FGF receptor 1 kinase domain (FGFR1K) (15) have provided details on the molecular mechanisms by which RTKs are kept in a low activity state prior to autophosphorylation of A-loop tyrosines
Summary
The RTK family can be broadly divided into two groups depending on the covalent organization of the receptor. The conformation of the phosphorylated A-loop permits unrestricted access to the binding sites for ATP and protein substrates and facilitates the proper spatial arrangement of residues involved in MgATP coordination, namely the protein kinase-conserved lysine and glutamic acid from the N-terminal lobe (Lys1030 and Glu1047 in IRK) and the aspartic acid of the conserved Asp-Phe-Gly triad (Asp1150 in IRK). The insulin receptor (and most RTKs) can be activated in the absence of ligand by tyrosine phosphatase inhibitors such as vanadate, which can mimic some of the biological effects of insulin (20, 21), indicating that autoinhibition alone is not sufficient to keep RTKs quiescent It is clear from the crystallographic temperature factors (Bfactors) that segments of the unphosphorylated IRK and FGFR1K A-loops are relatively mobile, and an equilibrium between different conformations of the A-loop likely exists in vivo. These mutations shift the above mentioned A-loop equilibrium toward the active conformation
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