Intelectin Explained

Xenopus embryonic epidermal lectin
Organism:Xenopus laevis
Taxid:8355
Symbol:itln1
Entrezgene:398574
Homologene:111044
Pdb:4WN0
Refseqmrna:NM_001089101.1
Refseqprotein:NP_001082570.1
Uniprot:Q800K0
Human intelectin-1
Symbol:ITLN1
Altsymbols:hIntL-1
Entrezgene:55600
Hgncid:18259
Omim:609873
Pdb:4WMY
Refseq:NP_060095
Uniprot:Q8WWA0
Chromosome:1
Arm:q
Band:21.3

Intelectins are lectins (carbohydrate-binding proteins) expressed in humans and other chordates. Humans express two types of intelectins encoded by ITLN1 and ITLN2 genes respectively.[1] [2] Several intelectins bind microbe-specific carbohydrate residues. Therefore, intelectins have been proposed to function as immune lectins.[3] [4] Even though intelectins contain fibrinogen-like domain found in the ficolins family of immune lectins, there is significant structural divergence.[5] Thus, intelectins may not function through the same lectin-complement pathway. Most intelectins are still poorly characterized and they may have diverse biological roles. Human intelectin-1 (hIntL-1) has also been shown to bind lactoferrin,[6] but the functional consequence has yet to be elucidated. Additionally, hIntL-1 is a major component of asthmatic mucus[7] and may be involved in insulin physiology as well.[8]

Diversity

The first intelectin was discovered in Xenopus laevis oocyte and is named XL35 or XCGL-1.[9] [10] [11] X. laevis oocyte also contains a closely related XCGL-2.[12] In addition, X. laevis embryos secrete Xenopus embryonic epidermal lectin into the environmental water, presumably to bind microbes.[13] [14] XSL-1 and XSL-2 are also expressed in X. laevis serum when stimulated with lipopolysaccharide.[15] Two additional intestinal intelectins are discovered in X. laevis[16]

Human has two intelectins: hIntL-1 (omentin) and hIntL-2.[17] Mouse also has two intelectins: mIntL-1 and mIntL-2.[18]

Immune system

Several lines of evidence suggest that intelectins recognize microbes and may function as an innate immune defense protein. Tunicate intelectin is an opsonin for phagocytosis by hemocyte.[19] Amphioxus intelectin has been shown to agglutinate bacteria.[20] [21] In zebrafish and rainbow trout, intelectin expression is stimulated upon microbial exposure.[22] [23] [24] Mammals such as sheep and mice also upregulate intelectin expression upon parasitic infection.[25] [26] Increase in intelectin expression upon microbial exposure support the hypothesis that intelectins play a role in the immune system.

Structure

Although intelectins require calcium ion for function, the sequences bear no resemblance to C-type lectins. In addition, merely around 50 amino acids (the fibronogen-like domain) align with any known protein, specifically the ficolin family. The first structural details of an intelectin comes from the crystal structure of selenomethionine-labeled XEEL carbohydrate-recognition domain (Se-Met XEEL-CRD) solved by Se-SAD. XEEL-CRD was expressed and Se-Met-labeled in High Five insect cells using a recombinant baculovirus. The fibrinogen-like fold is conserved despite amino acid sequence divergence. However, extensive insertions are present in intelectin compared to ficolins, thus making intelectin a distinct lectin structural class. The Se-Met XEEL-CRD structure then enables the structure solution by molecular replacement of D-glycerol 1-phosphate (GroP)-bound XEEL-CRD, apo-human intelectin-1 (hIntL-1), and galactofuranose-bound hIntL-1.

Each polypeptide chain of XEEL and hIntL-1 contains three bound calcium ions: two in the structural calcium site and one in the ligand binding site. The amino acid residues in the structural calcium site are conserved among intelectins, thus it is likely that most, if not all, intelectins have two structural calcium ions.

In the ligand binding site of XEEL and hIntL-1, the exocyclic vicinal diol of the carbohydrate ligand directly coordinates to the calcium ion. There are large variations in the ligand binding site residues among intelectin homologs suggesting that the intelectin family may have broad ligand specificities and biological functions. As there is no intelectin numbering conventions in different organisms, one should not assume functional homology based on the intelectin number. For example, hIntL-1 has glutamic acid residues in the ligand binding site to coordinate a calcium ion, while zebrafish intelectin-1 are devoided of these acidic residues. Zebrafish intelectin-2 ligand binding site residues are similar to those present in hIntL-1.

Oligomeric state

hIntL-1 is a disulfide-linked trimer as shown by non-reducing SDS-PAGE and X-ray crystallography. Despite lacking the intermolecular disulfide bonds, XEEL-CRD is trimeric in solution. The N-terminal peptide of the full length XEEL is responsible for dimerizing the trimeric XEEL-CRD into a disulfide-linked hexameric full-length XEEL. Therefore, the N-termini of intelectins are often responsible for forming disulfide-linked oligomer. In intelectin homologs where the N-terminal cysteines are absent, the CRD itself may still capable of forming non-covalent oligomer in solution.

Further reading

Notes and References

  1. Lee JK, Baum LG, Moremen K, Pierce M . The X-lectins: a new family with homology to the Xenopus laevis oocyte lectin XL-35 . Glycoconjugate Journal . 21 . 8–9 . 443–50 . August 2004 . 15750785 . 10.1007/s10719-004-5534-6 . 10.1.1.537.3931 . 41789407 .
  2. Yan J, Xu L, Zhang Y, Zhang C, Zhang C, Zhao F, Feng L . Comparative genomic and phylogenetic analyses of the intelectin gene family: implications for their origin and evolution . Developmental and Comparative Immunology . 41 . 2 . 189–99 . Oct 2013 . 23643964 . 10.1016/j.dci.2013.04.016 .
  3. Tsuji S, Uehori J, Matsumoto M, Suzuki Y, Matsuhisa A, Toyoshima K, Seya T . Human intelectin is a novel soluble lectin that recognizes galactofuranose in carbohydrate chains of bacterial cell wall . The Journal of Biological Chemistry . 276 . 26 . 23456–63 . Jun 2001 . 11313366 . 10.1074/jbc.M103162200 . free .
  4. Wesener DA, Wangkanont K, McBride R, Song X, Kraft MB, Hodges HL, Zarling LC, Splain RA, Smith DF, Cummings RD, Paulson JC, Forest KT, Kiessling LL . Recognition of microbial glycans by human intelectin-1 . Nature Structural & Molecular Biology . 22 . 8 . 603–10 . Aug 2015 . 26148048 . 10.1038/nsmb.3053 . 4526365.
  5. Wangkanont K, Wesener DA, Vidani JA, Kiessling LL, Forest KT . Structures of Xenopus embryonic epidermal lectin reveal a conserved mechanism of microbial glycan recognition . The Journal of Biological Chemistry . Jan 2016 . 26755729 . 10.1074/jbc.M115.709212 . 291 . 11 . 5596–610. 4786701 . free .
  6. Suzuki YA, Shin K, Lönnerdal B . Molecular cloning and functional expression of a human intestinal lactoferrin receptor . Biochemistry . 40 . 51 . 15771–9 . Dec 2001 . 11747454 . 10.1021/bi0155899 .
  7. Kerr SC, Carrington SD, Oscarson S, Gallagher ME, Solon M, Yuan S, Ahn JN, Dougherty RH, Finkbeiner WE, Peters MC, Fahy JV . Intelectin-1 is a prominent protein constituent of pathologic mucus associated with eosinophilic airway inflammation in asthma . American Journal of Respiratory and Critical Care Medicine . 189 . 8 . 1005–7 . Apr 2014 . 24735037 . 10.1164/rccm.201312-2220LE . 4098098.
  8. Yang RZ, Lee MJ, Hu H, Pray J, Wu HB, Hansen BC, Shuldiner AR, Fried SK, McLenithan JC, Gong DW . Identification of omentin as a novel depot-specific adipokine in human adipose tissue: possible role in modulating insulin action . American Journal of Physiology. Endocrinology and Metabolism . 290 . 6 . E1253–61 . Jun 2006 . 16531507 . 10.1152/ajpendo.00572.2004 .
  9. Roberson MM, Barondes SH . Lectin from embryos and oocytes of Xenopus laevis. Purification and properties . The Journal of Biological Chemistry . 257 . 13 . 7520–4 . Jul 1982 . 10.1016/S0021-9258(18)34409-0 . 7085636 . free .
  10. Nishihara T, Wyrick RE, Working PK, Chen YH, Hedrick JL . Isolation and characterization of a lectin from the cortical granules of Xenopus laevis eggs . Biochemistry . 25 . 20 . 6013–20 . Oct 1986 . 3098282 . 10.1021/bi00368a027.
  11. Lee JK, Buckhaults P, Wilkes C, Teilhet M, King ML, Moremen KW, Pierce M . Cloning and expression of a Xenopus laevis oocyte lectin and characterization of its mRNA levels during early development . Glycobiology . 7 . 3 . 367–72 . Apr 1997 . 9147045 . 10.1093/glycob/7.3.367. free .
  12. Shoji H, Ikenaka K, Nakakita S, Hayama K, Hirabayashi J, Arata Y, Kasai K, Nishi N, Nakamura T . Xenopus galectin-VIIa binds N-glycans of members of the cortical granule lectin family (xCGL and xCGL2) . Glycobiology . 15 . 7 . 709–20 . Jul 2005 . 15761024 . 10.1093/glycob/cwi051 . free .
  13. Nagata S, Nakanishi M, Nanba R, Fujita N . Developmental expression of XEEL, a novel molecule of the Xenopus oocyte cortical granule lectin family . Development Genes and Evolution . 213 . 7 . 368–70 . Jul 2003 . 12802587 . 10.1007/s00427-003-0341-9 . 41996445 .
  14. Nagata S . Isolation, characterization, and extra-embryonic secretion of the Xenopus laevis embryonic epidermal lectin, XEEL . Glycobiology . 15 . 3 . 281–90 . Mar 2005 . 15537792 . 10.1093/glycob/cwi010 . free .
  15. Nagata S, Nishiyama S, Ikazaki Y . Bacterial lipopolysaccharides stimulate production of XCL1, a calcium-dependent lipopolysaccharide-binding serum lectin, in Xenopus laevis . Developmental and Comparative Immunology . 40 . 2 . 94–102 . Jun 2013 . 23454582 . 10.1016/j.dci.2013.02.008 .
  16. Nagata S . Identification and characterization of a novel intelectin in the digestive tract of Xenopus laevis . Developmental and Comparative Immunology . 59 . 229–239 . Feb 2016 . 26855011 . 10.1016/j.dci.2016.02.006 .
  17. Lee JK, Schnee J, Pang M, Wolfert M, Baum LG, Moremen KW, Pierce M . Human homologs of the Xenopus oocyte cortical granule lectin XL35 . Glycobiology . 11 . 1 . 65–73 . Jan 2001 . 11181563 . 10.1093/glycob/11.1.65 . free .
  18. Lu ZH, di Domenico A, Wright SH, Knight PA, Whitelaw CB, Pemberton AD . Strain-specific copy number variation in the intelectin locus on the 129 mouse chromosome 1 . BMC Genomics . 12 . 1 . 110 . 2011 . 21324158 . 10.1186/1471-2164-12-110 . 3048546 . free .
  19. Abe Y, Tokuda M, Ishimoto R, Azumi K, Yokosawa H . A unique primary structure, cDNA cloning and function of a galactose-specific lectin from ascidian plasma . European Journal of Biochemistry . 261 . 1 . 33–9 . Apr 1999 . 10103030 . 10.1046/j.1432-1327.1999.00238.x . free .
  20. Yan J, Wang J, Zhao Y, Zhang J, Bai C, Zhang C, Zhang C, Li K, Zhang H, Du X, Feng L . Identification of an amphioxus intelectin homolog that preferably agglutinates gram-positive over gram-negative bacteria likely due to different binding capacity to LPS and PGN . Fish & Shellfish Immunology . 33 . 1 . 11–20 . Jul 2012 . 22475783 . 10.1016/j.fsi.2012.03.023 . 35820556 .
  21. Yan J, Zhang C, Zhang Y, Li K, Xu L, Guo L, Kong Y, Feng L . Characterization and comparative analyses of two amphioxus intelectins involved in the innate immune response . Fish & Shellfish Immunology . 34 . 5 . 1139–46 . May 2013 . 23428515 . 10.1016/j.fsi.2013.01.017 .
  22. Lin B, Cao Z, Su P, Zhang H, Li M, Lin Y, Zhao D, Shen Y, Jing C, Chen S, Xu A . Characterization and comparative analyses of zebrafish intelectins: highly conserved sequences, diversified structures and functions . Fish & Shellfish Immunology . 26 . 3 . 396–405 . Mar 2009 . 19100836 . 10.1016/j.fsi.2008.11.019 .
  23. Russell S, Young KM, Smith M, Hayes MA, Lumsden JS . Identification, cloning and tissue localization of a rainbow trout (Oncorhynchus mykiss) intelectin-like protein that binds bacteria and chitin . Fish & Shellfish Immunology . 25 . 1–2 . 91–105 . Jul 2008 . 18502147 . 10.1016/j.fsi.2008.02.018 .
  24. Russell S, Hayes MA, Lumsden JS . Immunohistochemical localization of rainbow trout ladderlectin and intelectin in healthy and infected rainbow trout (Oncorhynchus mykiss) . Fish & Shellfish Immunology . 26 . 1 . 154–63 . Jan 2009 . 19046637 . 10.1016/j.fsi.2008.03.001 .
  25. Datta R, deSchoolmeester ML, Hedeler C, Paton NW, Brass AM, Else KJ . Identification of novel genes in intestinal tissue that are regulated after infection with an intestinal nematode parasite . Infection and Immunity . 73 . 7 . 4025–33 . Jul 2005 . 15972490 . 10.1128/IAI.73.7.4025-4033.2005 . 1168561.
  26. French AT, Knight PA, Smith WD, Brown JK, Craig NM, Pate JA, Miller HR, Pemberton AD . Up-regulation of intelectin in sheep after infection with Teladorsagia circumcincta . International Journal for Parasitology . 38 . 3–4 . 467–75 . Mar 2008 . 17983620 . 10.1016/j.ijpara.2007.08.015 .

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