Structure and function of LGR5: An enigmatic G-protein coupled receptor marking stem cells

Authors

  • Kaavya Krishna Kumar,

    1. Structural Biology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia
    2. Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia
    Search for more papers by this author
  • Antony W. Burgess,

    1. Structural Biology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia
    2. Department of Surgery, University of Melbourne, Parkville, Victoria, Australia
    Search for more papers by this author
  • Jacqueline M. Gulbis

    Corresponding author
    1. Structural Biology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia
    2. Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia
    • Correspondence to: Jacqueline M. Gulbis, Structural Biology Division, The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3052, Australia. E-mail: jgulbis@wehi.edu.au

    Search for more papers by this author

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.

Ancillary