Evolutionarily Conserved Paired Immunoglobulin-like Receptor α (PILRα) Domain Mediates Its Interaction with Diverse Sialylated Ligands

Abstract

Background: PILR␣ is an inhibitory receptor predominantly expressed in myeloid cells. Results: NPDC1 and COLEC12 are novel PILR␣ ligands. PILR␣ arginine residues 133 (mouse) and 126 (human) are critical contact residues. Conclusion: PILR␣/ligand interactions involve a conserved domain in PILR␣ and a sialylated protein domain in the ligand. Significance: PILR␣ interacts with various ligands to alter myeloid cell function.

PILRα Negatively Regulates Mouse Inflammatory Arthritis

“…A complex network of ligands expressed in a variety of tissues has been implicated in PILRa interactions (8)(9)(10). Although we do not fully understand the consequence of the interaction of PILRa with individual ligands, it is interesting that a conserved domain in PILRa is critical for its interaction with all known ligands, a property shared with the Siglec family of inhibitory receptors (9,43).…”

“…If this were the case, dissociation of the interaction between PILRa and its ligands would increase BMDC cytokine production. We showed previously that sialic acid is an essential component of PILRa ligands in primary cells, and treatment of primary cells with sialidase A, which cleaves sialic acid from surface proteins, abolished their binding to PILRa (9). Therefore, we used sialidase A treatment to dissociate PILRa-ligand interactions on BMDCs.…”

“…Anti-PILRa mAbs were generated from Armenian hamsters and Pilra 2/2 mice using immunogenic fusion proteins consisting of the extracellular domain of the mouse Pilra gene (GenBank accession number: NM_153510), including amino acid positions Met 1 to Val 197, as previously described (9). Mouse anti-PILRa mAbs are IgG1 isotype.…”

“…Specific sialylated O-linked glycans on ligands are required for their binding to PILRa (6,10,12). We recently identified two more binding partners of PILRa, neural proliferation differentiation and control-1 and collectin-12, and found that an evolutionarily conserved PILRa domain mediates its interaction with these diverse sialylated ligands (9). This suggests that a complex network of ligands might modulate cellular functions via PILRa.…”

“…PILRb has a truncated cytoplasmic domain and a charged amino acid residue in its transmembrane region that associates with the ITAM-bearing DAP12 adaptor molecule to deliver activating signals (8). Human and mouse PILRa share only ∼40% homology (7), yet conserved residues mediate ligand interactions (9).…”