New structural insights into lectin-type proteins of the immune system

Kogelberg, Heide; Feizi, Ten

doi:10.1016/s0959-440x(00)00259-1

Cited by 53 publications

(34 citation statements)

References 66 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The matching regions of these 15 structures all correspond to Ctype lectin-like folds (in most cases from proteins known to interact with carbohydrate), confirming its structural similarity to the Link module noted previously (10,34). The highest scoring match is with eosinophil granule major basic protein (EMBP), which is clearly a member of the C-type lectin superfamily (on the basis of sequence), but does not have a typical Ca 2ϩ /carbohydrate-binding site (35,36). Interestingly, EMBP has been shown to interact with the sulfated glycosaminoglycan heparin, and the basic residues implicated in binding (35) are found on an equivalent face of the protein as the HAbinding site in the TSG-6 Link module.…”

Section: Fig 2 Solution Structures Of the Tsg-6 Link Module In Its mentioning

confidence: 99%

The Link Module from Ovulation- and Inflammation-associated Protein TSG-6 Changes Conformation on Hyaluronan Binding

Blundell

Mahoney²,

Almond

et al. 2003

Journal of Biological Chemistry

256

View full text Add to dashboard Cite

The solution structure of the Link module from human TSG-6, a hyaladherin with important roles in inflammation and ovulation, has been determined in both its free and hyaluronan-bound conformations. This reveals a well defined hyaluronan-binding groove on one face of the Link module that is closed in the absence of ligand. The groove is lined with amino acids that have been implicated in mediating the interaction with hyaluronan, including two tyrosine residues that appear to form essential intermolecular hydrogen bonds and two basic residues capable of supporting ionic interactions. This is the first structure of a non-enzymic hyaladherin in its active state, and identifies a ligand-induced conformational change that is likely to be conserved across the Link module superfamily. NMR and isothermal titration calorimetry experiments with defined oligosaccharides have allowed us to infer the minimum length of hyaluronan that can be accommodated within the binding site and its polarity in the groove; these data have been used to generate a model of the complex formed between the Link module and a hyaluronan octasaccharide.Hyaluronan (HA), 1 a high molecular weight polysaccharide with a central role in extracellular matrix organization and cell adhesion in mammals (1), is essential to a wide range of normal physiological processes including development, immunology, and reproduction (2-4). Alterations in the metabolism and localization of this molecule underlie the progression of many diseases, for instance arthritis, pulmonary/vascular disorders, and cancer (5, 6). These diverse biological activities may seem surprising for a linear polymer composed entirely of a repeating disaccharide (i.e. -glucuronic acid-␤Ϫ1,3-N-acetylglucosamine-␤Ϫ1,4-; up to 10 7 Da) that, unlike other glycosaminoglycans, is neither attached to a core protein nor sulfated. This functional complexity is thought to arise from the interaction of HA with a large number of specific HA-binding proteins (7), which can form structurally diverse complexes (see Ref. 8). The majority of these "hyaladherins" belong to a superfamily of proteins that share a common ϳ100 amino acid domain, termed a Link module, that mediates the interaction with HA.Previously we have determined the solution structure of the Link module from human TSG-6 (the protein product of the tumor necrosis factor-stimulated gene-6 (9)), thereby defining the consensus fold for this superfamily (10). In TSG-6, a 35-kDa secreted protein composed mainly of contiguous Link and CUB modules, the Link module is sufficient to mediate a high affinity interaction with HA (10, 11); this has been termed a "type A" HA-binding domain (7). The HA receptor CD44, which has an important role in mediating lymphocyte migration, however, requires N-and C-terminal extensions to its Link module for correct folding and functional activity of its type B interaction domain. Most other members of the superfamily, such as link proteins and chondroitin-sulfate proteoglycans (critical for extracellular matrix organiza...

show abstract

Section: Fig 2 Solution Structures Of the Tsg-6 Link Module In Its mentioning

confidence: 99%

The Link Module from Ovulation- and Inflammation-associated Protein TSG-6 Changes Conformation on Hyaluronan Binding

Blundell

Mahoney²,

Almond

et al. 2003

Journal of Biological Chemistry

256

View full text Add to dashboard Cite

show abstract

“…Ly-49Rs belong to the C-type lectin superfamily that also includes the selectins and the collectins (48). The ␤4-␤5 loop may also play a functional role in defining specificity of other C-type lectins.…”

Section: Discussionmentioning

confidence: 99%

Reciprocal Transfer of Class I MHC Allele Specificity between Activating Ly-49P and Ly-49W Receptors by Exchange of β4–β5 Loop Residues

Brian

Silver

Hazes

et al. 2003

The Journal of Immunology

View full text Add to dashboard Cite

Receptors of the Ly-49 multigene family regulate rodent NK cell functions. Ly-49Rs are highly polymorphic and exist in either activating or inhibitory forms. Examples of both Ly-49 receptor types have been shown to recognize class I MHC ligands. Ly-49Rs can distinguish between class I alleles, but the molecular basis of this discrimination is unknown. Two activating receptors, Ly-49P and Ly-49W, differ in class I recognition, recognizing H-2Dd, or H-2Dd and Dk, respectively. In this report, we demonstrate that specificity for H-2Dk can be transferred from Ly-49W to Ly-49P by substituting 3 aa predicted to reside in the β4–β5 loop of Ly-49W into Ly-49P. Replacement of these same residues of Ly-49W with corresponding residues in Ly-49P eliminates H-2Dk recognition while still preserving H-2Dd recognition. Further mutagenesis indicates that all 3 aa facilitate optimal class I specificity exchange. These results provide the first evidence for a specific site on Ly-49Rs, the β4–β5 loop, in determining class I MHC allele specificity.

show abstract

“…This region contains a large number of genes that encode type II transmembrane proteins with C-type lectin and C-type-like lectin domains (1,17). C-type lectins are proteins that share a common sequence motif, the CRD, with 14 invariable and 18 highly conserved aa residues (2, 31) These lectins were initially defined as proteins involved in the recognition of oligosaccharides in a Ca 2ϩ -dependent manner via their CRD (2,31). A number of C-type lectins do not bind sugars due to a divergence from the prototype CRD (2).…”

Section: Discussionmentioning

confidence: 99%

“…3 These CRDs contain calcium-binding pockets that are essential for carbohydrate ligand binding (1). In addition, C-type lectin-like receptors have now been characterized, and these consist of a CRD-like domain that might bind protein or lipids rather than carbohydrates (2). There are two groups of membrane-bound, C-type lectins, distinguished on the basis of the orientation of their amino (N) terminus.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Dendritic Cell-Associated Lectin-1: A Novel Dendritic Cell-Associated, C-Type Lectin-Like Molecule Enhances T Cell Secretion of IL-4

Ryan

Marshall

Magaletti

et al. 2002

The Journal of Immunology

View full text Add to dashboard Cite

We have characterized dendritic cell (DC)-associated lectin-1 (DCAL-1), a novel, type II, transmembrane, C-type lectin-like protein. DCAL-1 has restricted expression in hemopoietic cells, in particular, DCs and B cells, but T cells and monocytes do not express it. The DCAL-1 locus is within a cluster of C-type lectin-like loci on human chromosome 12p12–13 just 3′ to the CD69 locus. The consensus sequence of the DCAL-1 gene was confirmed by RACE-PCR; however, based on sequence alignment with genomic DNA and with various human expressed sequence tags, we predict that DCAL-1 has two splice variants. C-type lectins share a common sequence motif of 14 invariable and 18 highly conserved aa residues known as the carbohydrate recognition domain. DCAL-1, however, is missing three of the cysteine residues required to form the standard carbohydrate recognition domain. DCAL-1 mRNA and protein expression are increased upon the differentiation of monocytes to CD1a+ DCs. B cells also express high levels of DCAL-1 on their cell surface. Using a DCAL-1 fusion protein we identified a population of CD4+ CD45RA+ T cells that express DCAL-1 ligand. Coincubation with soluble DCAL-1 enhanced the proliferation of CD4+ T cells in response to CD3 ligation and significantly increased IL-4 secretion. In contrast, coincubation with soluble DC-specific ICAM-3-grabbing nonintegrin (CD209) fusion protein as a control had no effect on CD4+ T cell proliferation or IL-4 and IFN-γ secretion. Therefore, the function of DCAL-1 on DCs and B cells may act as a T cell costimulatory molecule, which skews CD4+ T cells toward a Th2 response by enhancing their secretion of IL-4.

show abstract

New structural insights into lectin-type proteins of the immune system

Cited by 53 publications

References 66 publications

The Link Module from Ovulation- and Inflammation-associated Protein TSG-6 Changes Conformation on Hyaluronan Binding

The Link Module from Ovulation- and Inflammation-associated Protein TSG-6 Changes Conformation on Hyaluronan Binding

Reciprocal Transfer of Class I MHC Allele Specificity between Activating Ly-49P and Ly-49W Receptors by Exchange of β4–β5 Loop Residues

Dendritic Cell-Associated Lectin-1: A Novel Dendritic Cell-Associated, C-Type Lectin-Like Molecule Enhances T Cell Secretion of IL-4

Contact Info

Product

Resources

About