A Mollusk Retinoic Acid Receptor (RAR) Ortholog Sheds Light on the Evolution of Ligand Binding

• Tipo: Artigo em Revista Científica Internacional
• Data: 2014

Autores

Gutierrez Mazariegos, J (Autor) Outra; Nadendla, EK (Autor) Outra; Lima, D (Autor) Outra; Pierzchalski, K (Autor) Outra; Jones, JW (Autor) Outra; Kane, M (Autor) Outra; Nishikawa, JI (Autor) Outra; Hiromori, Y (Autor) Outra; Nakanishi, T (Autor) Outra; Santos, MM (Autor) FCUP; Filipe F C Castro (Autor) FCUP; Bourguet, W (Autor) Outra; Schubert, M (Autor) Outra; Laudet, V (Autor) Outra

Revista

Título: Endocrinology

Vol. 155

Páginas: 4275-4286

ISSN: 0013-7227

Editora: Endocrine Society

Indexação

ISI Web of Knowledge - 39 Citações

Scopus - 42 Citações

Outras Informações

ID Authenticus: P-009-WR9

DOI: 10.1210/en.2014-1181

Abstract (EN): Nuclear receptors are transcription factors that regulate networks of target genes in response to small molecules. There is a strong bias in our knowledge of these receptors because they were mainly characterized in classical model organisms, mostly vertebrates. Therefore, the evolutionary origins of specific ligand-receptor couples still remain elusive. Here we present the identification and characterization of a retinoic acid receptor (RAR) from the mollusk Nucella lapillus (NlRAR). We show that this receptor specifically binds to DNA response elements organized in direct repeats as a heterodimer with retinoid X receptor. Surprisingly, we also find that NlRAR does not bind all-trans retinoic acid or any other retinoid we tested. Furthermore, NlRAR is unable to activate the transcription of reporter genes in response to stimulation by retinoids and to recruit coactivators in the presence of these compounds. Three-dimensional modeling of the ligand-binding domain of NlRAR reveals an overall structure that is similar to vertebrate RARs. However, in the ligand-binding pocket (LBP) of the mollusk receptor, the alteration of several residues interacting with the ligand has apparently led to an overall decrease in the strength of the interaction with the ligand. Accordingly, mutations of NlRAR at key positions within the LBP generate receptors that are responsive to retinoids. Altogether our data suggest that, in mollusks, RAR has lost its affinity for all-trans retinoic acid, highlighting the evolutionary plasticity of its LBP. When put in an evolutionary context, our results reveal new structural and functional features of nuclear receptors validated by millions of years of evolution that were impossible to reveal in model organisms.

Idioma: Inglês

Tipo (Avaliação Docente): Científica

Nº de páginas: 12