In addition, the GAIN domain of GPR56 (a different cell-adhesion GPCR, mutations of which cause bilateral frontoparietal polymicrogyria (BFPP); Piao et al, 2004) is sufficient for autoproteolysis, suggesting that the GAIN domain mediates autoproteolysis in other cell-adhesion GPCRs as well.
Since most cancer mutations are located on the surface of the CL GAIN domains, they may be involved in the interaction of the GAIN domain with a ligand or with the nearby transmembrane helices.
Indeed, deletion of the extracellular sequences of GPR56, a cell-adhesion GPCR with an extracellular GAIN domain that is preceded only by a short non-GAIN domain sequence, causes constitutive activation of the GPCR (Paavola et al, 2011), suggesting a possible inhibitory role for the GAIN domain.
Computational analysis of the GAIN domain sequences showed that all cell-adhesion GPCRs and all PKD proteins have a GAIN domain with identical predicted secondary structure patterns to that of the CL1 and BAI3 crystal structures showing that the GAIN domain is widespread and conserved in higher eukaryotes as well as in ancient organisms (Supplementary Table S3).
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They also took more time to make a decision in the loss domain than in the gain domain (F 1, 22) = 7.77, p<0.05).
Moreover, the participants were risk averse in the gain domain and risk seeking for loss (Table 1: the variable giving the interaction between risk and loss is positive, P = 0.001), as predicted by Prospect Theory [32].
They were told that at the end of each task, two of their decisions would be randomly selected to be played for real (one in the gain domain and the other in the loss domain), and another random device would determine the outcomes of the selected bets.
Thus, the GAIN domain functions as an autoproteolytic fold.
To understand the mechanism of GAIN-domain catalysed autoproteolysis, we performed extensive mutagenesis of the CL1 GAIN domain.
