Intelectins

 

 

 

 

Xenopus laevis (left) and Xenopus tropicalis
Photo by Robert Grainger, University of Virginia
 
Introduction
 
Intelectins (also known as eglectins or X-lectins) were first described in the frog Xenopus laevis and are present in vertebrates and in chordate organisms which lie between vertebrates and invertebrates phylogenetically, such as ascidians (sea squirts).  Intelectins generally have a simple domain structure, consisting of a single intelectin carbohydrate recognition domain (CRD) with a variable-length, non-conserved N-terminal extension containing a signal sequence for protein secretion.  The intelectin CRD is not related in sequence to any known protein domain, with the exception of ~45 residues at the N-terminus, which exhibit similarity to the globular domain of fibrinogen.  The CRD in lectins of the ficolin group is also similar to the fibrinogen globular domain, but in this case the similarity is present along the entire length of the domain.  Intelectins and ficolins are not closely related and exhibit distinct ligand binding specificities, expression patterns and structural organization.  Members of the intelectin group can be identified by a unique and very highly conserved sequence motif (GGWTLVASVHEN or similar), which spans the novel and fibrinogen-like regions of the domain.  The pattern of evolution within the intelectin family is unclear, but it appears that a single ancestral intelectin may have undergone differential expansion in different lineages.  The intelectins within a taxon (eg fish, amphibians and mammals) are more closely related to one another than to proteins from other taxa, suggesting that there are no one-to-one orthologies between intelectins from different species, except in species which are very closely related.  In humans and other primates, two intelectin genes are present in tandem on chromosome 1.  Intelectins are also present in the equivalent region of rodent genomes.  In lower organisms - fish, amphibians and sea squirts - a number of intelectin genes are spread over multiple chromosomes.  Intelectins are secreted proteins, and in some cases are known to be stored in secretory granules or anchored to the membrane by modification with glycosylphosphatidyl inositol anchors.  They generally form disulphide-linked homo-oligomers, which may increase ligand binding affinity, and there is evidence of Ca2+-dependent sugar binding activity in a number of proteins across the family.  Intelectins are suggested to have roles in innate immunity, recognizing pathogen-associated glycans, and in fertilization and embryogenesis, recognizing endogenous carbohydrate ligands.  At least some intelectins are N-glycosylated and the attached glycans may be ligands for other types of lectin.
 
Intelectins in Xenopus
 
There are at least five intelectins in Xenopus laevis: xCGL (cortical granule lectin, XL35), xCGL2, xEEL (embryonic epidermal lectin), xSL (35kDa serum lectin) and xSL2 (lectin type 2).  xCGL exists as a disulphide-linked homo-oligomer, possibly consisting of 12 polypeptides, and exhibits Ca2+-dependent binding to a broad range of galactose-terminating oligosaccharides.  xCGL is the major protein in oocyte secretory vesicles (cortical granules), which fuse with the plasma membrane at fertilization, releasing xCGL into the oocyte protein coat (the vitelline layer).  The protein coat contains large mucin-like glycoproteins which present O-linked glycans bearing terminal alpha-linked galactose residues that are bound by xCGL.  The aggregation of lectin and glycoprotein forms the fertilization layer, which prevents binding of further sperm to the egg and protects the developing embryo.  xCGL is likely to have additional functions after fertilization.  Both xCGL and xCGL2 are expressed throughout early embryogenesis and bear biantennary glycans with polylactosamine extensions that are ligands for galectin VIIa.  Unidentified GPI-anchored homologs of xCGL are involved in sugar-dependent cell-cell adhesion in Xenopus embryos.  xEEL exists as disulphide-bonded homohexamers and exhibits Ca2+-dependent binding to galactose and to a range of other monosaccharides, with a preference for pentoses over hexoses, but no affinity for disaccharides.  xEEL is secreted by epidermal cells in the embryo, with secretion levels increasing significantly around the time of hatching and being maintained for several days, suggesting that the protein may protect embryos and larvae against pathogens in the environmental water. xSL and xSL2 are found in serum and may be related to a previously described serum protein with similarity to xCGL that exhibits Ca2+-dependent binding to galactose.  Several putative intelectin genes are present in the genome of the closely related frog X tropicalis, but it is not yet clear if they represent orthologs of the X laevis intelectins. 
 
Intelectins in mammals
 
Humans have two intelectins, here termed intelectins -1 and -2.  Intelectin-1 has been described under the names of intelectin, endothelial lectin HL-1, intestinal lactoferrin receptor, and omentin.  Intelectin-2 is also known as endothelial lectin HL-2.  Intelectin-2 is expressed only in the small intestine, whereas intelectin-1 is found in a range of tissues, including the small intestine, where the site of expression has been further defined as Paneth cells, goblet cells and enterocytes.  This expression pattern suggests a role for the intelectins as host defence molecules in the small intestine.  Intelectin-1 forms disulphide-linked homotrimers, at least a proportion of which are modified with glycosylphoshatidyl inositol anchors in some tissues.  Intelectin-1 exhibits Ca2+-dependent binding to galactose and to GalNAc and several pentoses.  It notably binds D-galactofuranose residues in arabinogalactan from the cell wall of the bacterium Nocardia ruba.  Galactofuranose is the five-membered ring form of galactose and is found in a variety of microorganisms but not in mammals, which synthesize only the six-membered ring form, galactopyranose.  Recognition of non-mammalian sugars is suggestive of a role in pathogen recognition.  Intelectin-1 is also an intestinal receptor for lactoferrin, an iron-binding protein found principally in milk, which is known to have antimicrobial effects and to function in fertilization and early embryogenesis.  Lactoferrin binding is Ca2+-dependent, but it is not known if it is dependent on the N-glycosylation of lactoferrin.  Finally, when secreted by stromal vascular cells in certain adipose tissues, intelectin-1 functions as a signalling molecule which acts on adipocytes to enhance insulin-stimulated glucose uptake and stimulate intracellular protein phosphorylation by Akt kinase. 
 
Two intelectins have been characterized in mouse, here termed intelectins -a and -b.  The sequences of these proteins suggest they were produced by a separate gene duplication event to that which gave rise to the two primate intelectins, and it is not clear if there is functional equivalence between the mouse and human intelectins.  Intelectin-a (also known as intelectin or intelectin-1) is expressed in Paneth cells and is suggested to have a role in host defence.  Intelectin-b (intelectin-2) is induced in goblet and Paneth cells as part of the innate immune response to infection by a nematode parasite in BALB/c mice, which are resistant to nematode infection.  The gene is absent in C57BL/10 mice, which are susceptible to nematode infection.  Putative intelectin genes are present in other mammalian genomes, but the number varies between species.
 
Intelectins in other animals
 
The most primitive organisms known to express intelectins are the ascidians.  An intelectin from the hemolymph of the ascidian Halocynthia roretzi exhibits similar properties to human intelectin-1 and frog xCGL and xEEL.  The intelectin forms disulphide-bonded oligomers which bind to galactose, and functions as a pathogen recognition molecule in the innate immune system, enhancing phagocytosis by hemocytes and stimulating defence responses.  A transcript detected in the hemocytes of the ascidian Ciona intestinalis encodes a protein which, unusually, has a large insertion in the intelectin domain.  A number of putative intelectin genes are present in the genomes of Ciona intestinalis and Ciona savignyi.  Two intelectin sequences have been reported from the Japanese lamprey, a very early-branching vertebrate which lacks jaws.
 

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This page last updated:
Wednesday, 01 January 2014
Animal lectins home
Contact information: This site is supported by:
 
Kurt Drickamer
Division of Molecular Biosciences
Faculty of Natural Sciences
Imperial College London
 
Email: k.drickamer@imperial.ac.uk