Recombinant Human PEAR1 Protein, CF

Platelet endothelial aggregation receptor 1 (PEAR1) is a 150 kDa type I transmembrane protein and member of the MEGF family of proteins (1). Human PEAR1 is synthesized as a 1037 amino acid (aa) precursor that contains a 20 aa signal sequence, a 735 aa extracellular domain (ECD), a 21 aa transmembrane region, and a 261 aa cytoplasmic region (SwissProt # Q5VY43). The ECD consists of 15 EGF-like repeats that vary in length from 39 to 42 aa and contain a consensus sequence of CX_1-2GX₂GX_2-4CX₃CX_1-3CX_1-2GX_1-2CX₄GX₁CX₁CX₂GX₂GX₂C (1). The consensus repeat contains six conserved glycine residues and eight conserved cysteine residues, suggesting four disulfide-bonded cysteine pairs in each EGF repeat (1). Within the ECD, there are also five potential sites for N-linked glycosylation. The cytoplasmic region contains five potential Src homology 3-binding, proline-rich domains (1). Mature human PEAR1 is 84% aa identical to mature mouse PEAR1.  PEAR1 is most highly expressed in platelets and endothelial cells (1). High affinity immunoglobulin E receptor subunit  alpha (Fc epsilonR1 alpha) has been identified as an activating platelet endothelium aggregation receptor 1 (PEAR1) ligand. The signaling enhances and stabilizes platelet aggregates, which leads to tyrosine-phosphorylation of PEAR1 (2). Phosphorylation of PEAR1 is inhibited by the alpha_IIb beta₃ antagonist eptifibatide, thus demonstrating that PEAR1 tyrosine phosphorylation is dependent on surface contacts between activated platelets (1). PEAR1 can be phosphorylated in an alpha_IIb beta₃ integrin-dependent manner on tyrosine (Tyr925) and serine residues (Ser593 and Ser1029) and, potentially, at Tyr804, Tyr943, and Tyr979 (1). Sushi, von Willebrand factor type A, EFG and pentraxin domain containing 1 (SVEP1) has also been identified as a high affinity ligand for PEAR1 and this interaction promotes disease associated AKT/mTOR signaling in vascular cells and platelets (3). Inherited PEAR1 variations that alter expression or function of the platelet signaling molecule could modify agonist-induced aggregation in native platelets (3). In addition, a genetic variant in PEAR1 could be an important determinant of residual platelet function during aspirin treatment, because the COX1/thromboxane A2 pathway will be strongly inhibited by aspirin, and maximal aggregation will then be dependent on other secondary signaling pathways (4).