Role of the Cys(18)-Cys(274) disulfide bond and of the third extracellular loop in the constitutive activation and internalization of angiotensin II type 1 receptor

Role of the Cys(18)-Cys(274) disulfide bond and of the third extracellular loop in the constitutive activation and internalization of angiotensin II type 1 receptor

Autor Corrêa, Silvana Aparecida Alves Autor UNIFESP Google Scholar
Pignatari, G. C. Google Scholar
Ferro, E. S. Google Scholar
Pacheco, NAS Google Scholar
Costa-Neto, C. M. Google Scholar
Pesquero, J. B. Google Scholar
Oliveira, L. Google Scholar
Paiva, ACM Google Scholar
Shimuta, S. I. Google Scholar
Instituição Universidade Federal de São Paulo (UNIFESP)
Universidade de São Paulo (USP)
Fac Med Ribeirao Preto
Resumo An insertion of residues in the third extracellular loop and a disulfide bond linking this loop to the N-tenninal domain were identified in a structural model of a G-protein coupled receptor specific to angiotensin II (AT(1) receptor), built in homology to the seven-transmembrane-helix bundle of rhodopsin. Both the insertion and the disulfide bond were located close to an extracellular locus, flanked by the second extracellular loop (EC-2), the third extracellular loop (EC-3) and the N-terminal domain of the receptor; they contained residues identified by mutagenesis studies to bind the angiotensin II N-terminal segment (residues D-1 and R-2). It was postulated that the insertion and the disulfide bond, also found in other receptors such as those for bradykinin, endothelin, purine and other ligands, might play a role in regulating the function of the AT(1) receptor. This possibility was investigated by assaying AT(1) forms devoid of the insertion and with mutations to Ser on both positions of Cys residues forming the disulfide bond. Binding and activation experiments showed that abolition of this bond led to constitutive activation, decay of agonist binding and receptor activation levels. Furthermore, the receptors thus mutated were translocated to cytosolic environments including those in the nucleus. the receptor form with full deletion of the EC-3 loop residue insertion, displayed a wild type receptor behavior. (c) 2006 Elsevier B.V All rights reserved.
Palavra-chave AT(1) receptor mutations
GFP fusion proteins
constitutively active receptor
internalization
molecular modeling
Idioma Inglês
Data de publicação 2006-05-15
Publicado em Regulatory Peptides. Amsterdam: Elsevier B.V., v. 134, n. 2-3, p. 132-140, 2006.
ISSN 0167-0115 (Sherpa/Romeo, fator de impacto)
Publicador Elsevier B.V.
Extensão 132-140
Fonte http://dx.doi.org/10.1016/j.regpep.2006.02.008
Direito de acesso Acesso restrito
Tipo Artigo
Web of Science WOS:000237889300010
Endereço permanente http://repositorio.unifesp.br/handle/11600/28910

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