title: Evolutionarily conserved paired immunoglobulin-like receptor α (PILRα) domain mediates its interaction with diverse sialylated ligands.
abstract: Paired immunoglobulin-like receptor (PILR) α is an inhibitory receptor that recognizes several ligands, including mouse CD99, PILR-associating neural protein, and Herpes simplex virus-1 glycoprotein B. The physiological function(s) of interactions between PILRα and its cellular ligands are not well understood, as are the molecular determinants of PILRα/ligand interactions. To address these uncertainties, we sought to identify additional PILRα ligands and further define the molecular basis for PILRα/ligand interactions. Here, we identify two novel PILRα binding partners, neuronal differentiation and proliferation factor-1 (NPDC1), and collectin-12 (COLEC12). We find that sialylated O-glycans on these novel PILRα ligands, and on known PILRα ligands, are compulsory for PILRα binding. Sialylation-dependent ligand recognition is also a property of SIGLEC1, a member of the sialic acid-binding Ig-like lectins. SIGLEC1 Ig domain shares ∼22% sequence identity with PILRα, an identity that includes a conserved arginine localized to position 97 in mouse and human SIGLEC1, position 133 in mouse PILRα and position 126 in human PILRα. We observe that PILRα/ligand interactions require conserved PILRα Arg-133 (mouse) and Arg-126 (human), in correspondence with a previously reported requirement for SIGLEC1 Arg-197 in SIGLEC1/ligand interactions. Homology modeling identifies striking similarities between PILRα and SIGLEC1 ligand binding pockets as well as at least one set of distinctive interactions in the galactoxyl-binding site. Binding studies suggest that PILRα recognizes a complex ligand domain involving both sialic acid and protein motif(s). Thus, PILRα is evolved to engage multiple ligands with common molecular determinants to modulate myeloid cell functions in anatomical settings where PILRα ligands are expressed.
authors.affiliation: Department of Immunology, Genentech, South San Francisco, California 94080, USA.
authors.forename: Yonglian
authors.initials: Y
authors.lastname: Sun
authors.forename: Kate
authors.initials: K
authors.lastname: Senger
authors.forename: Tomasz K
authors.initials: TK
authors.lastname: Baginski
authors.forename: Anita
authors.initials: A
authors.lastname: Mazloom
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Chinn
authors.forename: Homer
authors.initials: H
authors.lastname: Pantua
authors.forename: Kajal
authors.initials: K
authors.lastname: Hamidzadeh
authors.forename: Sree Ranjani
authors.initials: SR
authors.lastname: Ramani
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Luis
authors.forename: Irene
authors.initials: I
authors.lastname: Tom
authors.forename: Andrew
authors.initials: A
authors.lastname: Sebrell
authors.forename: Gabriel
authors.initials: G
authors.lastname: Quinones
authors.forename: Yan
authors.initials: Y
authors.lastname: Ma
authors.forename: Kiran
authors.initials: K
authors.lastname: Mukhyala
authors.forename: Tao
authors.initials: T
authors.lastname: Sai
authors.forename: Jiabing
authors.initials: J
authors.lastname: Ding
authors.forename: Benjamin
authors.initials: B
authors.lastname: Haley
authors.forename: Hooman
authors.initials: H
authors.lastname: Shadnia
authors.forename: Sharookh B
authors.initials: SB
authors.lastname: Kapadia
authors.forename: Lino C
authors.initials: LC
authors.lastname: Gonzalez
authors.forename: Philip E
authors.initials: PE
authors.lastname: Hass
authors.forename: Ali A
authors.initials: AA
authors.lastname: Zarrin
mesh_terms: D000071443:12E7 Antigen; D000595:Amino Acid Sequence; D000818:Animals; D015703:Antigens, CD / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D001120:Arginine / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D001665:Binding Sites / Q000235:genetics; D015815:Cell Adhesion Molecules / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D037222:Collectins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D017124:Conserved Sequence / Q000235:genetics; D019143:Evolution, Molecular; D057809:HEK293 Cells; D006801:Humans; D008024:Ligands; D008562:Membrane Glycoproteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008958:Models, Molecular; D008969:Molecular Sequence Data; D019158:N-Acetylneuraminic Acid / Q000737:chemistry / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011971:Receptors, Immunologic / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D051116:Receptors, Scavenger / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D063267:Sialic Acid Binding Ig-like Lectin 1; D014709:Vero Cells
chemical_list: D000071443:12E7 Antigen; D015703:Antigens, CD; C061828:CD99 protein, human; C422442:COLEC12 protein, human; D015815:Cell Adhesion Molecules; D037222:Collectins; D008024:Ligands; D008562:Membrane Glycoproteins; C484270:NPDC1 protein, human; D009419:Nerve Tissue Proteins; C412263:PILRA protein, human; D011971:Receptors, Immunologic; D051116:Receptors, Scavenger; C571166:SIGLEC1 protein, human; D063267:Sialic Acid Binding Ig-like Lectin 1; C571167:Siglec1 protein, mouse; D001120:Arginine; D019158:N-Acetylneuraminic Acid