PRR repeats in the intracellular domain of KISS1R are important for its export to cell membrane. - Inserm - Institut national de la santé et de la recherche médicale Accéder directement au contenu
Article Dans Une Revue Mol Endocrinol Année : 2013

PRR repeats in the intracellular domain of KISS1R are important for its export to cell membrane.

Résumé

Inactivating mutations of KISS-1 receptor (KISS1R) have been recently described as a rare cause of isolated hypogonadotropic hypogonadism transmitted as a recessive trait. Few mutations have been described, and the structure-function relationship of KISS1R remains poorly understood. Here, we have taken advantage of the discovery of a novel mutation of KISS1R to characterize the structure and function of an uncommon protein motif composed of 3 proline-arginine-arginine (PRR) repeats located within the intracellular domain. A heterozygous insertion of 1 PRR repeat in-frame with 3 PRR repeats leading to synthesis of a receptor bearing 4 PRR repeats (PRR-KISS1R) was found in the index case. Functional analysis of PRR-KISS1R showed a decrease of the maximal response to kisspeptin stimulation, associated to a lower cell surface expression without modification of total expression. PRR-KISS1R exerts a dominant negative effect on the synthesis of the wild-type (WT)-KISS1R. This effect was due to the nature of inserted residues but also to the difference of the length of the intracellular domain between PRR-KISS1R and WT-KISS1R. A molecular dynamic analysis showed that the additional PRR constrained this arginine-rich region into a polyproline type II helix. Altogether, this study shows that a heterozygous insertion in KISS1R may lead to hypogonadotropic hypogonadism by a dominant negative effect on the WT receptor. An additional PRR repeat into a proline-arginine-rich motif can dramatically changed the conformation of the intracellular domain of KISS1R and its probable interaction with partner proteins.
Fichier principal
Vignette du fichier
Chevrier_MolEnd_2013_preprint.pdf (772.54 Ko) Télécharger le fichier
Chevrier_MolEnd_2013_supdata.pdf (208.72 Ko) Télécharger le fichier
Origine : Fichiers produits par l'(les) auteur(s)
Format : Autre
Loading...

Dates et versions

inserm-00926577 , version 1 (23-04-2014)

Identifiants

Citer

Lucie Chevrier, Alexandre de Brevern, Eva Hernandez, Jérome Leprince, Hubert Vaudry, et al.. PRR repeats in the intracellular domain of KISS1R are important for its export to cell membrane.: PRR repeats in intracellular domain of KISSIR. Mol Endocrinol, 2013, 27 (6), pp.1004-14. ⟨10.1210/me.2012-1386⟩. ⟨inserm-00926577⟩
678 Consultations
369 Téléchargements

Altmetric

Partager

Gmail Facebook X LinkedIn More