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

Mol Endocrinol. 2013 Jun;27(6):1004-14. doi: 10.1210/me.2012-1386. Epub 2013 Apr 22.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Animals
  • Base Sequence
  • COS Cells
  • Cell Membrane / metabolism*
  • Chlorocebus aethiops
  • DNA Mutational Analysis
  • Gene Expression
  • Genetic Association Studies
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Hypogonadism / genetics
  • Male
  • Molecular Dynamics Simulation
  • Molecular Sequence Data
  • Mutagenesis, Insertional
  • Obesity / genetics
  • Proline-Rich Protein Domains
  • Protein Transport
  • Receptors, G-Protein-Coupled / chemistry
  • Receptors, G-Protein-Coupled / genetics
  • Receptors, G-Protein-Coupled / metabolism*
  • Receptors, Kisspeptin-1

Substances

  • KISS1R protein, human
  • Receptors, G-Protein-Coupled
  • Receptors, Kisspeptin-1