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Journal of Endocrinology (2009) 201, 297-307       DOI: 10.1677/JOE-08-0527
© 2009 Society for Endocrinology
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Conformational effects of Lys191 in the human GnRH receptor: mutagenesis and molecular dynamics simulations studies

 Eduardo Jardón-Valadez1,2,*, Arturo Aguilar-Rojas1,*, Guadalupe Maya-Núñez1, Alfredo Leaños-Miranda1, Ángel Piñeiro2,3, P Michael Conn1,4 and Alfredo Ulloa-Aguirre1,4

1 Research Unit in Reproductive Medicine, Hospital de Ginecobstetricia ‘Luis Castelazo Ayala’, Instituto Mexicano del Seguro Social, Apartado Postal 99-065, Unidad Independencia, Mexico D.F. CP 10101, Mexico2 Departamento de Fisicoquímica, Facultad de Química, Universidad Nacional Autónoma de México, C.U., México D.F. CP04510, Mexico3 Departamento de Física Aplicada, Facultad de Física, Universidad de Santiago de Compostela, E-15782 Santiago de Compostela, Spain4 Oregon National Primate Research Center, Beaverton, 97006 Oregon, USA

(Correspondence should be addressed to A Ulloa-Aguirre; Email: aulloaa{at}servidor.unam.mx)

* (E Jardón-Valadez and A Aguilar-Rojas contributed equally to this work)

In the present study, we analyzed the role of Lys191 on function, structure, and dynamic behavior of the human GnRH receptor (hGnRHR) and the formation of the Cys14–Cys200 bridge, which is essential for receptor trafficking to the plasma membrane. Several mutants were studied; mutants lacked either the Cys14–Cys200 bridge, Lys191 or both. The markedly reduced expression and function of a Cys14Ser mutant lacking the 14–200 bridge, was nearly restored to wild-type/{Delta}Lys191 levels upon deletion of Lys191. Lys191 removal resulted in changes in the dynamic behavior of the mutants as disclosed by molecular dynamics simulations: the distance between the sulfur- (or oxygen-) sulfur groups of Cys (or Ser)14 and Cys200 was shorter and more constant, and the conformation of the NH2-terminus and the exoloop 2 exhibited fewer fluctuations than when Lys191 was present. These data provide novel information on the role of Lys191 in defining an optimal configuration for the hGnRHR intracellular trafficking and function.






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