Abstract
The large family of C-type lectin (CLEC) receptors comprises carbohydrate-binding proteins that require Ca2+ to bind a ligand. The prototypic receptor is the asialoglycoprotein receptor-1 (ASGR1, CLEC4H1) that is expressed primarily by hepatocytes. The early work on ASGR1, which is highly specific for N-acetylgalactosamine (GalNAc), established the foundation for understanding the overall function of CLEC receptors. Cells of the immune system generally express more than one CLEC receptor that serve diverse functions such as pathogen-recognition, initiation of cellular signaling, cellular adhesion, glycoprotein turnover, inflammation and immune responses. The receptor CLEC10A (C-type lectin domain family 10 member A, CD301; also called the macrophage galactose-type lectin, MGL) contains a carbohydrate-recognition domain (CRD) that is homologous to the CRD of ASGR1, and thus, is also specific for GalNAc. CLEC10A is most highly expressed on immature DCs, monocyte-derived DCs, and alternatively activated macrophages (subtype M2a) as well as oocytes and progenitor cells at several stages of embryonic development. This receptor is involved in initiation of TH1, TH2, and TH17 immune responses and induction of tolerance in naïve T cells. Ligand-mediated endocytosis of CLEC receptors initiates a Ca2+ signal that interestingly has different outcomes depending on ligand properties, concentration, and frequency of administration. This review summarizes studies that have been carried out on these receptors.
Highlights
ASGR1 and CLEC10A are members of a large group of proteins called ‘lectins’ that non-enzymatically bind carbohydrate structures
Research over the past four decades identified a vast number of lectin receptors in mammalian tissues, which function as surveillance of the extensive glycome in normal tissues, recognition of environmental danger signals, cell-cell adhesion, ligand-specific endocytosis, glycoprotein turnover, and mediators of inflammation and immune responses
Five major families of lectin-type receptors have been cataloged: the I-type Siglec receptors are specific for glycan ligands that contain terminal sialic acid [1,2,3]; galectins bind ligands that contain β-galactoside moieties [4,5]; F-type lectins bind fucose [6]; and R-type lectins resemble the protein ricin [7]
Summary
ASGR1 and CLEC10A are members of a large group of proteins called ‘lectins’ that non-enzymatically bind carbohydrate structures. Whereas the initial insertion of Ca2+ occurs during folding of the protein within the endoplasmic reticulum, the continuous recycling of the receptor over several hours indicates that the CRD is recharged repeatedly with Ca2+ upon exposure to the extracellular fluid This intuition is supported by the refolding of recombinant CRD of ASGR1 after expression in Escherichia coli. The Ca2+ concentration within the endosome drops rapidly [47], and as it is lowered below about 330 μM, the KD of the two ‘high’ affinity Ca2+ binding sites in the CRD and with a reduced pH of 6.9, the ligand dissociates This condition is achieved in about 3 min [47,48]. The cell has several mechanisms to control cytosolic Ca2+ concentrations near 0.1 μM, a transient elevation in the concentration induced by ligand-mediated recycling of the receptor initiates Ca2+-dependent signaling pathways within the cell
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
