title: Structure and function of LGR5: an enigmatic G-protein coupled receptor marking stem cells.
abstract: G-protein coupled receptors (GPCRs) are an important class of membrane protein that transmit extracellular signals invoked by sensing molecules such as hormones and neurotransmitters. GPCR dysfunction is implicated in many diseases and hence these proteins are of great interest to academia and the pharmaceutical industry. Leucine-rich repeat-containing GPCRs contain a characteristic extracellular domain that is an important modulator of intracellular signaling. One member of this class is the leucine-rich repeat-containing G-protein-coupled receptor 5 (LGR5), a stem cell marker in intestinal crypts, and mammary glands. LGR5 modulates Wnt signaling in the presence of the ligand R-spondin (RSPO). The mechanism of activation of LGR5 by RSPO is not understood, nor is the intracellular signaling mechanism known. Recently reported structures of the extracellular domain of LGR5 bound to RSPO reveal a horseshoe-shaped architecture made up of consecutive leucine-rich repeats, with RSPO bound on the concave surface. This review discusses the discovery of LGR5 and the impact it is having on our understanding of stem cell and cancer biology of the colon. In addition, it covers functional relationships suggested by sequence homology and structural analyses, as well as some intriguing conundrums with respect to the involvement of LGR5 in Wnt signaling.
authors.affiliation: Structural Biology Division, The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria, 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, Victoria, 3052, Australia.
authors.forename: Kaavya Krishna
authors.initials: KK
authors.lastname: Kumar
authors.forename: Antony W
authors.initials: AW
authors.lastname: Burgess
authors.forename: Jacqueline M
authors.initials: JM
authors.lastname: Gulbis
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D003110:Colonic Neoplasms / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011487:Protein Conformation; D043562:Receptors, G-Protein-Coupled / Q000737:chemistry* / Q000378:metabolism*; D015398:Signal Transduction; D013234:Stem Cells / Q000737:chemistry / Q000378:metabolism*; D019699:Thrombospondins / Q000378:metabolism; D060449:Wnt Signaling Pathway
chemical_list: C116884:LGR5 protein, human; D043562:Receptors, G-Protein-Coupled; D019699:Thrombospondins
keywords: GPCR; LGR5; RSPO; Wnt signaling; colon cancer; stem cells