Insulin receptor Arg717 and IGF-1 receptor Arg704 play a key role in ligand binding and in receptor activation

0577780 - ÚOCHB 2024 RIV GB eng J - Článek v odborném periodiku
Kertisová, Anna - Žáková, Lenka - Macháčková, Kateřina - Marek, Aleš - Šácha, Pavel - Pompach, Petr - Jiráček, Jiří - Selicharová, Irena
Insulin receptor Arg717 and IGF-1 receptor Arg704 play a key role in ligand binding and in receptor activation.
Open Biology. Roč. 13, č. 11 (2023), č. článku 230142. E-ISSN 2046-2441
Grant CEP: GA MŠMT(CZ) LX22NPO5104; GA MŠMT(CZ) EF16_019/0000729; GA ČR(CZ) GA22-17978S; GA MŠMT(CZ) EF18_046/0015974; GA MŠMT LM2023042
Institucionální podpora: RVO:61388963 ; RVO:86652036
Klíčová slova: mutagenesisin vitro * peptide hormone * eceptor modification * eceptor tyrosine kinase * structure–function
Obor OECD: Biochemistry and molecular biology
Impakt faktor: 5.8, rok: 2022
Způsob publikování: Open access
https://doi.org/10.1098/rsob.230142

The insulin receptor (IR, with its isoforms IR-A and IR-B) and the insulin-like growth factor 1 receptor (IGF-1R) are related tyrosine kinase receptors. Recently, the portfolio of solved hormone–receptor structures has grown extensively thanks to advancements in cryo-electron microscopy. However, the dynamics of how these receptors transition between their inactive and active state are yet to be fully understood. The C-terminal part of the alpha subunit (αCT) of the receptors is indispensable for the formation of the hormone-binding site. We mutated the αCT residues Arg717 and His710 of IR-A and Arg704 and His697 of IGF-1R. We then measured the saturation binding curves of ligands on the mutated receptors and their ability to become activated. Mutations of Arg704 and His697 to Ala in IGF-1R decreased the binding of IGF-1. Moreover, the number of binding sites for IGF-1 on the His697 IGF-1R mutant was reduced to one-half, demonstrating the presence of two binding sites. Both mutations of Arg717 and His710 to Ala in IR-A inactivated the receptor. We have proved that Arg717 is important for the binding of insulin to its receptor, which suggests that Arg717 is a key residue for the transition to the active conformation.
Trvalý link: https://hdl.handle.net/11104/0346886