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Alanine scanning mutagenesis of the second extracellular loop of type 1 corticotropin-releasing factor receptor revealed residues critical for peptide binding.
Gkountelias, Kostas; Tselios, Theodoros; Venihaki, Maria; Deraos, George; Lazaridis, Iakovos; Rassouli, Olga; Gravanis, Achille; Liapakis, George.
Afiliação
  • Gkountelias K; Department of Pharmacology, Faculty of Medicine, University of Crete, Heraklion, Crete, Greece.
Mol Pharmacol ; 75(4): 793-800, 2009 Apr.
Article em En | MEDLINE | ID: mdl-19124613
Upon binding of the corticotropin-releasing factor (CRF) analog sauvagine to the type 1 CRF receptor (CRF(1)), the amino-terminal portion of the peptide has been shown to lie near Lys257 in the receptor's second extracellular loop (EL2). To test the hypothesis that EL2 residues play a role in the binding of sauvagine to CRF(1) we carried out an alanine-scanning mutagenesis study to determine the functional role of EL2 residues (Leu251 to Val266). Only the W259A, F260A, and W259A/F260A mutations reduced the binding affinity and potency of sauvagine. In contrast, these mutations did not seem to significantly alter the overall receptor conformation, in that they left unchanged the affinities of the ligands astressin and antalarmin that have been suggested to bind to different regions of CRF(1). The W259A, F260A, and W259A/F260A mutations also decreased the affinity of the endogenous ligand, CRF, implying that these residues may play a common important role in the binding of different peptides belonging to CRF family. Parallel amino acid deletions of the two peptides produced ligands with various affinities for wild-type CRF(1) compared with the W259A, F260A, and W259A/F260A mutants, supporting the interaction between the amino-terminal residues 8 to 10 of sauvagine and the corresponding region in CRF with EL2 of CRF(1). This is the first time that a specific region of CRF(1) has been implicated in detailed interactions between the receptor and the amino-terminal portion of peptides belonging to the CRF family.
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Fragmentos de Peptídeos / Mutagênese Sítio-Dirigida / Receptores de Hormônio Liberador da Corticotropina / Alanina Limite: Humans Idioma: En Revista: Mol Pharmacol Ano de publicação: 2009 Tipo de documento: Article País de afiliação: Grécia País de publicação: Estados Unidos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Fragmentos de Peptídeos / Mutagênese Sítio-Dirigida / Receptores de Hormônio Liberador da Corticotropina / Alanina Limite: Humans Idioma: En Revista: Mol Pharmacol Ano de publicação: 2009 Tipo de documento: Article País de afiliação: Grécia País de publicação: Estados Unidos