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001-es BibID:	BIBFORM087409
Első szerző:	Hajdu Tímea (biomérnök)
Cím:	Comprehensive Model for Epidermal Growth Factor Receptor Ligand Binding Involving Conformational States of the Extracellular and the Kinase Domains / Tímea Hajdu, Tímea Váradi, István Rebenku, Tamás Kovács, János Szöllösi, Péter Nagy
Dátum:	2020
ISSN:	2296-634X
Megjegyzések:	The epidermal growth factor (EGF) receptor (EGFR) undergoes ligand-dependent dimerization to initiate transmembrane signaling. Although crystallographic structures of the extracellular and kinase domains are available, ligand binding has not been quantitatively analyzed taking the influence of both domains into account. Here, we developed a model explicitly accounting for conformational changes of the kinase and extracellular domains, their dimerizations and ligand binding to monomeric and dimeric receptor species. The model was fitted to ligand binding data of suspended cells expressing receptors with active or inactive kinase conformations. Receptor dimers with inactive, symmetric configuration of the kinase domains exhibit positive cooperativity and very weak binding affinity for the first ligand, whereas dimers with active, asymmetric kinase dimers are characterized by negative cooperativity and subnanomolar binding affinity for the first ligand. The homodimerization propensity of EGFR monomers with active kinase domains is _100-times higher than that of dimers with inactive kinase domains. Despite this fact, constitutive, ligand-independent dimers are mainly generated from monomers with inactive kinase domains due to the excess of such monomers in the membrane. The experimental finding of increased positive cooperativity at high expression levels of EGFR was recapitulated by the model. Quantitative prediction of ligand binding to different receptor species revealed that EGF binds to receptor monomers and dimers in an expression-level dependent manner without significant recruitment of monomers to dimers upon EGF stimulation below the phase transition temperature of the membrane. Results of the fitting offer unique insight into the workings of the EGFR.
Tárgyszavak:	Természettudományok Biológiai tudományok idegen nyelvű folyóiratközlemény külföldi lapban folyóiratcikk EGF EGFR
Megjelenés:	Frontiers in Cell and Developmental Biology. - 8 (2020), p. 1-53. -
További szerzők:	Váradi Tímea (1973-) (biológus) Rebenku István Kovács Tamás (1985-) (általános orvos) Szöllősi János (1953-) (biofizikus) Nagy Péter (1971-) (biofizikus)
Pályázati támogatás:	GINOP-2.3.2-15-2016-00020 GINOP GINOP-2.2.1-15-2017-00044 GINOP NKFIH K120302 Egyéb
Internet cím:	Szerző által megadott URL DOI Intézményi repozitóriumban (DEA) tárolt változat
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