Review
I-type lectins

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Abstract

The immunoglobulin superfamily is a large category of proteins defined by their structural similarity to immunoglobulins. The majority of these proteins are involved in protein–protein binding as receptors, antibodies or cell adhesion molecules. The I-type lectins are a subset of the immunoglobulin superfamily that are capable of carbohydrate–protein interactions. There are I-type lectins recognizing sialic acids, other sugars and glycosaminoglycans. The occurrence, structure, binding properties and (potential) biological functions of the I-type lectins are reviewed here.

Introduction

“I-type lectin” is a collective term introduced by Powell and Varki [1] to describe carbohydrate-recognizing proteins that belong to the immunoglobulin (Ig) superfamily. This classification is somewhat broader compared with C-type lectins [2], [3], [4], [5], [6], [7] or S-type lectins (or galectins [8], [9], [10], [11], [12], [13]), which are defined by conserved amino acid residues in their carbohydrate-recognition domains (CRDs).

Although a small number of proteins with an Ig-like domain (two β-sheets stacked together and cross-linked by a disulfide bond) are found in bacteria [14], Ig superfamily proteins have greatly expanded during the evolution of multicellular animals (metazoa), and acquired great sequence divergence. As a result, it is sometimes difficult to recognize by sequence comparison that two randomly selected Ig-like domains are phylogenetically related (the same applies to other “successful” protein structures, such as (β/α)8 barrel structure shared by many enzymes). Many cell adhesion molecules belong to Ig superfamily [15], [16], and I-type lectins account for a small fraction of them. However, it is unknown if all I-type lectins have arisen from a recent common ancestor, or if different branches of Ig superfamily proteins have independently acquired lectin functions by functional convergence.

Ig-like domains are classified into three different “sets”, i.e. V-set, C1-set, and C2-set, based on the number and arrangement of β-strands present in the domain [15]. We followed this traditional classification in this review, but recent studies suggest the presence of “I-set” domains (an intermediate form between V-set and C-set), and many of the Ig-like domains previously classified as C2-set are now reclassified into this I-set [16]. With the advance of three-dimensional structural analysis of proteins, further revision of domain classification may be required in the future.

In the following section, we will review the properties of I-type lectins. We are deliberately inclusive in the selection of the molecules to be reviewed, i.e. any protein with Ig-like domain and reported lectin-like properties was included, unless its CRD is known not to be in the Ig-like domain. Also, proteins that bind to sulfated glycosaminoglycans are usually not considered as “lectins”, but we will provide a brief overview of Ig superfamily proteins that show distinct binding to sulfated glycosaminoglycans.

Section snippets

I-type lectins recognizing sialic acids

Quite a number of I-type lectins specifically recognize sialic acids. Sialic acids are acidic monosaccharides frequently found at the outer end of secreted and cell surface glycoconjugates, an optimal location for recognition by lectins. More than 40 different forms of sialic acid exist and they can be attached in a variety of linkages to the underlying sugar, creating a huge degree of molecular diversity [17], [18], [19], [20]. Among the I-type lectins recognizing sialic acids are the Siglecs

I-type lectins recognizing other sugars

Several Ig superfamily proteins reportedly recognize glyococonjugates in a sialic acid-independent manner. These molecules lack a recognizable common sequence motif defining carbohydrate binding, and do not share binding specificity either, hence not to be considered as a cohesive subfamily of I-type lectins.

It is tempting to include the Receptor for Advanced Glycation Endproducts (RAGE) [183] in this group of molecules, because of the fact that probes used in the search of binding proteins for

Immunoglobulin superfamily proteins that recognize sulfated glycosaminoglycans

As mentioned earlier, proteins interacting with sulfated glycosaminoglycans (GAGs) are generally not considered as “lectins”, perhaps because the binding is dictated predominantly by charge interactions. However, some proteins show selectivity towards the type of GAGs they interact with (in many cases heparin/heparan sulfate are the favored ligands). Hence, we include a brief overview of this class of molecules. Platelet–endothelial cell adhesion molecule-1 (PECAM-1) was also considered as one

Concluding remarks

Many Ig superfamily proteins have been shown to interact with carbohydrates in the past decade, and new members will undoubtedly join this family of I-type lectins in the future. Finding new members of I-type lectins, as well as discovering carbohydrate binding properties of known Ig superfamily proteins, will continue to be important aspects of glycobiology. However, the relevance of carbohydrate recognition in the biological functions of these molecules has not been extensively studied so

Acknowledgements

We thank Dr. Ajit Varki for valuable discussions and comments on the manuscript.

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