Comparative genomics of leucine-rich repeats containing G protein-coupled receptors and their ligands

Abstract

Leucine-rich repeats containing G protein-coupled receptors (LGRs) constitute a unique cluster of transmembrane proteins sharing a large leucine-rich extracellular domain for hormone binding. In mammals, LGRs steer important developmental, metabolic and reproductive processes as receptors for glycoprotein hormones and insulin/relaxin-related proteins. In insects, a receptor structurally related to human LGRs mediates the activity of the neurohormone bursicon thereby regulating wing expansion behaviour and remodelling of the newly synthesized exoskeleton. In the past decade, novel insights into the molecular evolution of LGR encoding genes accumulated rapidly due to comparative genome analyses indicating that the endocrine LGR signalling system likely emerged before the radiation of metazoan phyla and expanded throughout evolution. Here, we present a short survey on the evolution of LGRs and the hormones they interact with.

Introduction

G protein-coupled receptors (GPCRs) are transmembrane proteins that respond to a diverse array of stimuli [e.g., light, odorants, taste molecules, lipid analogous, amines, nucleotides, peptides and protein hormones] and transmit these signals intracellularly through activation of heterotrimeric G proteins (Joost and Methner, 2002). Genome analyses identified GPCRs as one of the largest functional protein “superfamilies” with about eight hundred human GPCRs (Bjarnadottir et al. 2006), one thousand in the nematode, Caenorhabditis elegans (Bargmann, 1998) and two hundred in the fruit fly, Drosophila melanogaster (Brody and Cravchik, 2000, Vanden Broeck, 2001a). The majority of GPCRs is believed to act as olfactory receptors, while a distinct subset regulates developmental processes as receptors for peptide or protein hormones.

GPCRs share several key structural features, i.e., seven α-helical membrane-spanning segments interconnected by three intra- and extracellular loops (the “serpentine region”) and an intracellular C-terminal tail. Within the large rhodopsin-like receptor family (“family A GPCRs”), leucine-rich repeats containing GPCRs (LGRs) constitute a distinct subgroup characterized by a peculiar protein architecture. A true hallmark for LGRs is the large N-terminal extracellular (ecto-)domain involved in selective hormone binding (Braun et al. 1991) that is composed of tandem arrays of leucine-rich repeat (LRR) amino acid motifs, N- and C-terminally flanked by cysteine-rich sequences (Kajava, 1998). A so-called hinge region connects this ectodomain with the serpentine region.

In mammals, LGRs mediate the activity of large glycoprotein hormones, i.e., gonadotropins [follicle stimulating hormone (FSH), luteinizing hormone (LH), choriogonadotropin (CG)] and thyroid stimulating hormone (TSH) and, in consequence, have long been known to act as key players in the endocrine regulation of reproduction (gonadotropins) and metabolism (TSH) (Grossmann et al., 1997, Themmen and Huhtaniemi, 2000). Recently, genomic approaches forced us to revise the evolution of the LGR signalling system. Novel insights into the molecular evolution of LGR encoding genes emerged and demonstrated that LGRs predate the divergence of major animal phyla and expanded throughout metazoan evolution. Here, we present an overview of recent accomplishments illustrating the molecular evolution of the LGR/hormone endocrine system in metazoans.