title: 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.
authors.affiliation: Research Center for Glycoscience, National Institute of Advanced Industrial Science and Technology, 1-1-1 Umezono, Tsukuba, Ibaraki 305-8568, Japan. takashi-angata@aist.go.jp
authors.forename: Takashi
authors.initials: T
authors.lastname: Angata
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Hayakawa
authors.forename: Masahiro
authors.initials: M
authors.lastname: Yamanaka
authors.forename: Ajit
authors.initials: A
authors.lastname: Varki
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Nakamura
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D015703:Antigens, CD / Q000235:genetics* / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000235:genetics* / Q000378:metabolism; D001120:Arginine / Q000235:genetics; D019143:Evolution, Molecular; D005785:Gene Conversion; D006801:Humans; D037102:Lectins / Q000235:genetics* / Q000378:metabolism; D008565:Membrane Proteins; D011134:Polysaccharides / Q000378:metabolism; D011323:Primates; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011956:Receptors, Cell Surface / Q000235:genetics*; D011971:Receptors, Immunologic / Q000235:genetics / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D037102:Lectins; D008565:Membrane Proteins; D011134:Polysaccharides; D011956:Receptors, Cell Surface; D011971:Receptors, Immunologic; C514213:SIGLEC14 protein, human; C114531:SIGLEC5 protein, human; C110546:TYROBP protein, human; C092488:sialic acid receptor; D001120:Arginine