A putative mechanism for downregulation of the catalytic activity of the EGF receptor via direct contact between its kinase and C-terminal domains.
Tyrosine kinase receptors of the EGFR family play a significant role in vital cellular processes and in various cancers. EGFR members are unique among kinases, as the regulatory elements of their kinase domains are constitutively ready for catalysis. Nevertheless, the receptors are not constantly active. This apparent paradox has prompted us to seek mechanisms of regulation in EGFR's cytoplasmic domain that do not involve conformational changes of the kinase domain. Our computational analyses, based on the three-dimensional structure of EGFR's kinase domain suggest that direct contact between the kinase and a segment from the C-terminal regulatory domains inhibits enzymatic activity. EGFR activation would then involve temporal dissociation of this stable complex, for example, via ligand-induced contact formation between the extracellular domains, leading to the reorientation of the transmembrane and intracellular domains. The model provides an explanation at the molecular level for the effects of several cancer-causing EGFR mutations.
Landau
Meytal
M
Department of Biochemistry, George S. Wise Faculty of Life Sciences, Tel-Aviv University, Ramat-Aviv 69978, Israel.
Fleishman
Sarel J
SJ
Ben-Tal
Nir
N
D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D015536:Down-Regulation; D066246:ErbB Receptors / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D006860:Hydrogen Bonding; D008969:Molecular Sequence Data; D017434:Protein Structure, Tertiary; D055672:Static Electricity
D066246:ErbB Receptors