Movement of Activator of G‐Protein Signaling 3 within the Aggresome Pathway

Abstract

AGS3, a receptor independent activator of G‐protein signaling, is involved in unexpected functional diversity for G‐protein signaling systems. AGS3 has seven tetratricopeptide (TPR) motifs upstream of four G‐protein regulatory (GPR) motifs, each of which bind and stabilizes the GDP bound conformation of Giα. The positioning of AGS3 within the cell and the intra‐molecular dynamics between different domains of the proteins are likely key determinants of their ability to influence G‐protein signaling. We report that AGS3 enters into the aggresome pathway and that this positioning of the protein is differentially regulated by the AGS3 binding partners Giα and mInsc. Giα rescues AGS3 from the aggresome, whereas mInsc augments the aggresomal distribution of AGS3. The distribution of AGS3 to the aggresome is dependent upon the TPR domain and it is accelerated by disruption of the TPR organizational structure or introduction of a non‐synonymous single nucleotide polymorphism. These data present AGS3, G‐proteins and mInsc as candidate proteins involved in regulating cellular stress associated with protein processing pathologies.