Siglecs (sialic acid-binding immunoglobulin superfamily lectins)
	Siglecs are a family of immunoglobulin (Ig) superfamily lectins that recognize glycans containing sialic acids. Sialoadhesin/Siglec-1, CD22/Siglec-2, CD33/Siglec-3, and myelin-associated glycoproteins (MAG)/Siglec-4 were the original members of this family, and many new members have been recently identified. In humans, there are 11 Siglecs and a Siglec-like molecule (see Figure). Fugu (pufferfish) genome contains putative MAG ortholog, suggesting that the origin of Siglecs predates or coincides with the emergence of vertebrates. Structure Siglecs are type I transmembrane proteins, consisting of N-terminal V-set Ig-like domain, variable numbers (1~16) of C2-set Ig-like domains, a transmembrane domain and a cytosolic tail. The first Ig-like domain is the most crucial for the recognition of sialic acids. A few amino acid residues in the first Ig-like domain are well-conserved, such as an arginine on beta-strand F, two aromatic amino acids (one located near the N-terminal, the other downstream of the conserved arginine), and three cysteines, one of which forms an inter-domain disulfide bond with a cysteine in the second Ig-like domain. The conserved arginine forms a salt bridge with a carboxyl group of sialic acid, and mutations at this residue diminish sialic acid recognition. CD33-related Siglec subgroup All Siglecs except for Sialoadhesin, CD22 and MAG belong to the CD33-related Siglec subgroup, which is defined by high sequence similarity. Genes for the most of these Siglecs are clustered in a defined chromosomal region (Siglec gene cluster). In humans, this cluster is localized on the qarm of chromosome 19, while in mouse it is found on chromosome 7. There are 7 Siglec genes and numerous Siglec-like pseudogenes in human Siglec gene cluster, while there are only 4 Siglec genes and 2 Siglec-like pseudogenes in the mouse syntenic region. This suggests that archetypes of CD33-related Siglecs were established before the primate-rodent split (~100 million years ago), yet have undergone different evolutionary paths in different lineages/species. Distribution Sialoadhesin is expressed on tissue macrophages, CD22 on B-cells, and MAG on myelinating cells. Many CD33-related Siglecs are expressed on the cells involved in innate immunity, such as granulocytes, monocytes/macrophages, and NK cells. No two Siglecs show exactly the same expression pattern, suggesting that each of them plays a unique role. Biological functions Biological functions of some Siglecs have been studied using mutant (knock-out) animal models. CD22 is involved in negative regulation of B-cell activities, and MAG is involved in the maintenance of myelin sheath. Animal models for other Siglec deficiencies are currently being generated and studied. Most Siglecs function as signal transduction molecules. Studies correlating sialic acid recognition and signal transduction by Siglecs have been reported, but mechanistic details are still unclear.
	Takashi Angata (University of California at San Diego)
	References (1) Crocker,P.R., and Varki,A. (2001) Trends Immunol. 22, 337-342. (2) Angata,T., and Brinkman-van der Linden,E.C.M (2002) Biochim. Biophys. Acta 1572, 294-316. (3) Crocker,P.R. (2002) Curr. Opin. Struct. Biol. 12, 609-615.
Jan. 22, 2003