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Accepted Preprint first posted online on 26 February 2009

Journal of Endocrinology 2009;201:297.

Journal of Endocrinology (2009) In press
DOI: 10.1677/JOE-08-0527
© 2009 Society for Endocrinology
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RESEARCH

Conformational Effects of Lys191 in the Human Gonadotrophin-Releasing Hormone Receptor (hGnRHR). Mutagenesis and Molecular Dynamics Simulations Studies.

 Eduardo Jardon-Valadez, Arturo Aguilar-Rojas, Guadalupe Maya-Nunez, Alfredo Leanos-Miranda, Angel Pineiro, P Michael Conn and Alfredo Ulloa-Aguirre

E Jardon-Valadez, Research Unit in Reproductive Medicine, IMSS, Mexico City, Mexico
A Aguilar-Rojas, Mexico City, Mexico
G Maya-Nunez, Mexico City, Mexico
A Leanos-Miranda, Mexico City, Mexico
A Pineiro, Facultad de Fisica, Universidad de Santiago de Compostela, Santiago de Compostela, Spain
P Conn, 505 NW 185th Avenue, Oregon National Primate Research Center, Beaverton, United States
A Ulloa-Aguirre, Research Unit in Reproductive Medicine, IMSS, Mexico City, 10101, Mexico

Correspondence: Alfredo Ulloa-Aguirre, Email: aulloaa{at}servidor.unam.mx

Abstract

In the present study, we analyzed the role of Lys191 on function, structure, and dynamic behavior of the 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/desLys191 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 less 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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