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Título: | The role of the calmodulin-binding and calmodulin-like domains of the epidermal growth factor receptor in tyrosine kinase activation |
Autor: | Abdelli, Faten; Jellali, Karim CSIC; Anguita, Estefanía CSIC; González-Muñoz, María CSIC; Villalobo, Eduardo CSIC ORCID; Madroñal, Iván; Alcalde Gómez, Juan; Ben Ali, Mamdouh; Elloumi-Mseddi, Jihene; Jemel, Ikram; Tebar, Francesc; Enrich, Carlos; Aifa, Sami; Villalobo, Antonio CSIC ORCID | Palabras clave: | Calmodulin Calmodulin‐binding domain Calmodulin‐like domain Epidermal growth factorreceptor Receptor internalization Tyrosine kinase activity |
Fecha de publicación: | jul-2021 | Editor: | Wiley-Liss | Citación: | Journal of Cellular Physiology 236(7): 4997-5011 (2021) | Resumen: | The epidermal growth factor receptor (EGFR) harbors a calmodulin (CaM)-binding domain (CaM-BD) and a CaM-like domain (CaM-LD) upstream and downstream, respectively, of the tyrosine kinase (TK) domain. We demonstrate in this paper that deletion of the positively charged CaM-BD (EGFR/CaM-BD∆) inactivated the TK activity of the receptor. Moreover, deletion of the negatively charged CaM-LD (EGFR/CaM-LD∆), leaving a single negative residue (glutamate), reduced the activity of the receptor. In contrast, substituting the CaM-LD with a histidine/valine-rich peptide (EGFR/InvCaM-LD) caused full inactivation. We also demonstrated using confocal microscopy and flow cytometry that the chimera EGFR-green fluorescent protein (GFP)/CaM-BD∆, the EGFR/CaM-LD∆, and EGFR/InvCaM-LD mutants all bind tetramethylrhodamine-labelled EGF. These EGFR mutants were localized at the plasma membrane as the wild-type receptor does. However, only the EGFR/CaM-LD∆ and EGFR/InvCaM-LD mutants appear to undergo ligand-dependent internalization, while the EGFR-GFP/CaM-BD∆ mutant seems to be deficient in this regard. The obtained results and in silico modelling studies of the asymmetric structure of the EGFR kinase dimer support a role of a CaM-BD/CaM-LD electrostatic interaction in the allosteric activation of the EGFR TK. | Versión del editor: | http://dx.doi.org/10.1002/jcp.30205 | URI: | http://hdl.handle.net/10261/265583 | DOI: | 10.1002/jcp.30205 | ISSN: | 0021-9541 | E-ISSN: | 1097-4652 |
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