Structural conservation of ligand binding reveals a bile acid-like signaling pathway in nematodes.
J Biol Chem
; 287(7): 4894-903, 2012 Feb 10.
Article
em En
| MEDLINE
| ID: mdl-22170062
ABSTRACT
Bile acid-like molecules named dafachronic acids (DAs) control the dauer formation program in Caenorhabditis elegans through the nuclear receptor DAF-12. This mechanism is conserved in parasitic nematodes to regulate their dauer-like infective larval stage, and as such, the DAF-12 ligand binding domain has been identified as an important therapeutic target in human parasitic hookworm species that infect more than 600 million people worldwide. Here, we report two x-ray crystal structures of the hookworm Ancylostoma ceylanicum DAF-12 ligand binding domain in complex with DA and cholestenoic acid (a bile acid-like metabolite), respectively. Structure analysis and functional studies reveal key residues responsible for species-specific ligand responses of DAF-12. Furthermore, DA binds to DAF-12 mechanistically and is structurally similar to bile acids binding to the mammalian bile acid receptor farnesoid X receptor. Activation of DAF-12 by cholestenoic acid and the cholestenoic acid complex structure suggest that bile acid-like signaling pathways have been conserved in nematodes and mammals. Together, these results reveal the molecular mechanism for the interplay between parasite and host, provide a structural framework for DAF-12 as a promising target in treating nematode parasitism, and provide insight into the evolution of gut parasite hormone-signaling pathways.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Ácidos e Sais Biliares
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Proteínas de Helminto
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Colestenos
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Receptores Citoplasmáticos e Nucleares
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Ancylostoma
Idioma:
En
Ano de publicação:
2012
Tipo de documento:
Article
País de afiliação:
Estados Unidos