A human platelet receptor protein microarray identifies the high affinity immunoglobulin E receptor subunit α (FcεR1α) as an activating platelet endothelium aggregation receptor 1 (PEAR1) ligand

Yi Sun, C Vandenbriele, A Kauskot , P Verhamme, MF Hoylaerts, Gavin Wright

Research output: Contribution to journalArticlepeer-review

34 Citations (Scopus)
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Abstract

Genome-wide association studies to identify loci responsible for platelet function and cardiovascular disease susceptibility have repeatedly identified polymorphisms linked to a gene encoding platelet endothelium aggregation receptor 1 (PEAR1), an "orphan" cell surface receptor that is activated to stabilize platelet aggregates. To investigate how PEAR1 signaling is initiated, we sought to identify its extracellular ligand by creating a protein microarray representing the secretome and receptor repertoire of the human platelet. Using an avid soluble recombinant PEAR1 protein and a systematic screening assay designed to detect extracellular interactions, we identified the high affinity immunoglobulin E (IgE) receptor subunit α (FcεR1α) as a PEAR1 ligand. FcεR1α and PEAR1 directly interacted through their membrane-proximal Ig-like and 13th epidermal growth factor domains with a relatively strong affinity (KD ∼ 30 nm). Precomplexing FcεR1α with IgE potently inhibited the FcεR1α-PEAR1 interaction, and this was relieved by the anti-IgE therapeutic omalizumab. Oligomerized FcεR1α potentiated platelet aggregation and led to PEAR1 phosphorylation, an effect that was also inhibited by IgE. These findings demonstrate how a protein microarray resource can be used to gain important insight into the function of platelet receptors and provide a mechanistic basis for the initiation of PEAR1 signaling in platelet aggregation.
Original languageEnglish
Pages (from-to)1265-1274
Number of pages10
JournalMolecular and Cellular Proteomics
Volume14
Issue number5
DOIs
Publication statusPublished - 1 May 2015

Keywords

  • PEAR1
  • Protein Microarray
  • Protein interactions
  • AVEXIS

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