Discovery of Siglec‐14, a novel sialic acid receptor undergoing concerted evolution with Siglec‐5 in primates

Abstract

Immune receptors that show high mutual sequence similarity and have antagonizing signaling properties are called paired receptors, and are believed to fine-tune immune responses. Siglecs are sialic acid-recognizing receptors of the immunoglobulin (Ig) superfamily expressed on immune cells. Human Siglec-5, encoded by SIGLEC5 gene, has four extracellular Ig-like domains and a cytosolic inhibitory motif. We discovered human Siglec-14 with three Ig-like domains, encoded by the SIGLEC14 gene, adjacent to SIGLEC5. Human Siglec-14 has almost complete sequence identity with human Siglec-5 at the first two Ig-like domains, shows a glycan binding preference similar to that of human Siglec-5, and associates with the activating adapter protein DAP12. Thus, Siglec-14 and Siglec-5 appear to be the first glycan binding paired receptors. Near-complete sequence identity of the amino-terminal part of human Siglec-14 and Siglec-5 indicates partial gene conversion between SIGLEC14 and SIGLEC5. Remarkably, SIGLEC14 and SIGLEC5 in other primates also show evidence of gene conversions within each lineage. Evidently, balancing the interactions between Siglec-14, Siglec-5 and their common ligand(s) had selective advantage during the course of evolution. The "essential arginine" critical for sialic acid recognition in both Siglec-14 and Siglec-5 is present in humans but mutated in almost all great ape alleles.

Expression and preliminary functional analysis of Siglec-F on mouse macrophages

“…The majority of Siglec family members contain ITIMs within cytoplasmic domains (Angata et al, 2006;Cao et al, 2008). Typically, receptors with ITIMs function as inhibitory receptors and suppress activation signals that emanate from receptors associated with immunoreceptor tyrosine-based activation motifs (ITAMs) through recruitment of tyrosine and inositol phosphatases.…”

“…The specific binding of the extracellular domain of Siglecs to sialic acid residues on the glycosyl side-chains of glycolipids and glycoproteins mediates interactions with proteins and carbohydrates for a variety of purposes. The predominantly inhibitory function of the majority of Siglecs is indicated by the presence of immunoreceptor tyrosine-based inhibitory motifs (ITIMs) in the cytoplasmic domain (Angata et al, 2006;.…”

Genetic variants in PLG, LPA, and SIGLEC 14 as well as smoking contribute to plasma plasminogen levels

“…Like PLG and LPA, these genes are adjacent paralogs with extensive sequence similarities. 50 Siglec (sialic acid-binding Ig-like lectin) proteins have diverse biologic functions and serve as membrane-bound receptors for a large variety of sialyated glycoproteins. Siglec-5 may function as a clearance receptor for coagulation factor VIII and von Willebrand factor, 51 although no variant has been identified near SIGLEC5 in large GWAS or linkage studies for factor VIII and von Willebrand factor levels.…”

Mechanism and Function of Monoclonal Antibodies Targeting Siglec-15 for Therapeutic Inhibition of Osteoclastic Bone Resorption

“…Second, certain Siglecs contain a distinctive positively charged residue within their transmembrane domains that can interact with the trans-*All authors are current or former employees of Alethia Biotherapeutics. membrane immunoreceptor tyrosine-based activation motif (ITAM)-bearing co-receptors, such as DAP12 (10,11). DAP12 serves as a signaling module for a variety of immune receptors by recruiting the kinase Syk and other signaling molecules upon ligand binding to associated receptors (12,13).…”