Molecular basis for multimerization in the activation of the epidermal growth factor receptor
| Autor: | Shashank Bharill, Xiaojun Shi, Adam W. Smith, Ehud Y. Isacoff, Megan J. Kaliszewski, Seana M Peterson, Deepti Karandur, Yongjian Huang, John Kuriyan, Morgan Marita |
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| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Xenopus DNA Mutational Analysis Biochemistry biophysics structural biology 2.1 Biological and endogenous factors ERBB3 Epidermal growth factor receptor Phosphorylation Aetiology Biology (General) Cancer Kinase General Neuroscience Autophosphorylation General Medicine Biophysics and Structural Biology Single Molecule Imaging stoichiometry 3. Good health Cell biology ErbB Receptors Medicine Research Article Human QH301-705.5 1.1 Normal biological development and functioning EGFR Science Protein subunit Allosteric regulation Biology General Biochemistry Genetics and Molecular Biology 03 medical and health sciences Allosteric Regulation Underpinning research Animals biochemistry multimerization human Protein Processing General Immunology and Microbiology Post-Translational 030104 developmental biology Protein kinase domain Oocytes biology.protein Mutant Proteins Biochemistry and Cell Biology Protein Multimerization Phosphatidylinositol 3-Kinase Protein Processing Post-Translational |
| Zdroj: | Huang, Y; Bharill, S; Karandur, D; Peterson, SM; Marita, M; Shi, X; et al.(2016). Molecular basis for multimerization in the activation of the epidermal growth factor receptor. eLife, 5(MARCH2016). doi: 10.7554/eLife.14107. UC Berkeley: Retrieved from: http://www.escholarship.org/uc/item/4hb8p75r eLife, Vol 5 (2016) eLife, vol 5, iss MARCH2016 eLife |
| DOI: | 10.7554/eLife.14107. |
| Popis: | The epidermal growth factor receptor (EGFR) is activated by dimerization, but activation also generates higher-order multimers, whose nature and function are poorly understood. We have characterized ligand-induced dimerization and multimerization of EGFR using single-molecule analysis, and show that multimerization can be blocked by mutations in a specific region of Domain IV of the extracellular module. These mutations reduce autophosphorylation of the C-terminal tail of EGFR and attenuate phosphorylation of phosphatidyl inositol 3-kinase, which is recruited by EGFR. The catalytic activity of EGFR is switched on through allosteric activation of one kinase domain by another, and we show that if this is restricted to dimers, then sites in the tail that are proximal to the kinase domain are phosphorylated in only one subunit. We propose a structural model for EGFR multimerization through self-association of ligand-bound dimers, in which the majority of kinase domains are activated cooperatively, thereby boosting tail phosphorylation. DOI: http://dx.doi.org/10.7554/eLife.14107.001 |
| Databáze: | OpenAIRE |
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