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

Abstract : 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.
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https://www.hal.inserm.fr/inserm-00926577
Contributor : Alexandre G. de Brevern <>
Submitted on : Wednesday, April 23, 2014 - 9:22:57 AM
Last modification on : Tuesday, November 3, 2020 - 11:18:02 AM
Long-term archiving on: : Wednesday, July 23, 2014 - 10:40:30 AM

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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⟩

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