Membrane-association of EMR2/ADGRE2-NTF is regulated by site-specific N-glycosylation.

The evolutionarily conserved adhesion G protein-coupled receptors (aGPCRs) play critical roles in biological processes as diverse as brain development, cell polarity and innate immune functions. A defining feature of aGPCRs is the GPCR autoproteolysis inducing (GAIN) domain capable of self-catalytic cleavage, resulting in the generation of an extracellular N-terminal fragment (NTF) and a seven-transmembrane C-terminal fragment (CTF) involved in the cellular adhesion and signaling functions, respectively. Interestingly, two different NTF subtypes have previously been identified, namely an NTF that couples non-covalently with the CTF and a membrane-associated NTF that tethers on cell surface independently. The two NTF subtypes are expected to regulate aGPCR signaling via distinct mechanisms however their molecular characteristics are largely unknown. Herein, the membrane-associated NTF of EMR2/ADGRE2 is investigated and found to be modified by differential N-glycosylation. The membrane association of EMR2-NTF occurs in post-ER compartments and site-specific N-glycosylation in the GAIN domain is involved in modulating its membrane-association ability. Finally, a unique amphipathic α-helix in the GAIN domain is identified as a putative membrane anchor of EMR2-NTF. These results provide novel insights into the complex interaction and activation mechanisms of aGPCRs.

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