Molecular Characterization of the Signalling Activity and the Structural Organization of Emr2 Receptor in Myeloid Cells

The adhesion G protein-coupled receptor (GPCR) is characterized by a novel hybrid structure that contains a long N-terminal extracellular domain connected to a 7TM domain by a mucin-like spacer. Thus, they are also named the LNB-TM7 receptors. Based upon their unique structure, it has been suggested that the adhesion-GPCRs may play a role in the cellular functions by interacting with other cell surface or extracellular matrix proteins, leading to signal transduction via the 7TM domain. Indeed, the functional importance of the adhesion-GPCRs has been demonstrated in several human diseases such as Usher syndrome type II and bilateral frontoparietal polymicrogyria (BFPP). The majority of adhesion-GPCRs are also known to undergo a novel post-translational cleavage event at the GPCR proteolytic site (GPS) motif and express on the cell surface as a heterodimeric receptor composed of an extracellular α-subunit and a TM7 β-subunit. Therefore, it is believed that the commonly used GPS cleavage is highly relevant to the functions of the adhesion-GPCRs. We have recently identified the molecular mechanism of the GPS cleavage and shown that it is a self-catalyzed auto-proteolytic reaction. We and others have characterized a leukocyte-restricted subgroup of adhesion-GPCRs, called EGF-TM7 receptors, which contain tandem repeats of epidermal growth factor (EGF)-like domains at the N-terminal region. Recently, we have shown that EMR2, an EGF-TM7 molecule, can form homo- as well as hetero-dimers via a 7TM domain-mediated reaction. In addition, we also found that the ligation of EMR2 by antibody potentiates many neutrophil functions including adhesion, migration, and the release of antimicrobial mediators. This research proposal aims to investigate the signalling activities generated by the ligation of EMR2 receptor on Neutrophil and to further delineate the structural-functional relationship of the EMR2 receptor subunit organization. It is hoped that we can reveal the structural arrangement of EMR2 receptor subunits on the cell surface and demonstrate how the receptor subunit interaction in turn regulates EMR2 receptor signalling.

Project ID:PC10001-0091
External Project ID:NSC98-2320-B182-028-MY3