The model depicts how Gpr126/GPR126 function is regulated by its ECR. a Alternative splicing acts as a molecular switch to adopt different ECR conformations and have different basal levels of signaling. Gpr126 ECR that lacks the splice insert adopts a closed conformation and has basal activity, whereas Gpr126 ECR that includes the splice insert (magenta) is more dynamic and open-like, and has enhanced basal activity. Autoproteolysis in GAIN domain is indicated by a black asterisk. The calcium ion is shown as a bright green circle. b Mutation of conserved residues within the calcium-binding site leads to defects in both myelination and ear development in vivo. Human GPR126 function may also be regulated by furin cleavage, indicated by a green asterisk.
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