title: PRR repeats in the intracellular domain of KISS1R are important for its export to cell membrane.
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.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale Unité Mixte de Recherche 676, Hôpital Robert Debré, 48 Boulevard Sérurier, 75019 Paris, France.
authors.forename: Lucie
authors.initials: L
authors.lastname: Chevrier
authors.forename: Alexandre
authors.initials: A
authors.lastname: de Brevern
authors.forename: Eva
authors.initials: E
authors.lastname: Hernandez
authors.forename: Jérome
authors.initials: J
authors.lastname: Leprince
authors.forename: Hubert
authors.initials: H
authors.lastname: Vaudry
authors.forename: Anne Marie
authors.initials: AM
authors.lastname: Guedj
authors.forename: Nicolas
authors.initials: N
authors.lastname: de Roux
mesh_terms: D000293:Adolescent; D000818:Animals; D001483:Base Sequence; D019556:COS Cells; D002462:Cell Membrane / Q000378:metabolism*; D002522:Chlorocebus aethiops; D004252:DNA Mutational Analysis; D015870:Gene Expression; D056726:Genetic Association Studies; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D007006:Hypogonadism / Q000235:genetics; D008297:Male; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D016254:Mutagenesis, Insertional; D009765:Obesity / Q000235:genetics; D055232:Proline-Rich Protein Domains; D021381:Protein Transport; D043562:Receptors, G-Protein-Coupled / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000074502:Receptors, Kisspeptin-1
chemical_list: C118688:KISS1R protein, human; D043562:Receptors, G-Protein-Coupled; D000074502:Receptors, Kisspeptin-1