Distribution of activator of G-protein signaling 3 within the aggresomal pathway: role of specific residues in the tetratricopeptide repeat domain and differential regulation by the AGS3 binding partners Gi(alpha) and mammalian inscuteable.
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 that serve as docking sites for Gialpha-GDP. The positioning of AGS3 within the cell and the intramolecular 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 distribution of the protein is regulated by the AGS3 binding partners Gialpha and mammalian Inscuteable (mInsc). Gialpha rescues AGS3 from the aggresome, whereas mInsc augments the aggresome-like 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 nonsynonymous single-nucleotide polymorphism. These data present AGS3, G-proteins, and mInsc as candidate proteins involved in regulating cellular stress associated with protein-processing pathologies.
Vural
Ali
A
Department of Cell and Molecular Pharmacology and Experimental Therapeutics, Medical University of South Carolina, Charleston, South Carolina 29425, USA.
Oner
Sadik
S
An
Ningfei
N
Simon
Violaine
V
Ma
Dzwokai
D
Blumer
Joe B
JB
Lanier
Stephen M
SM
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D019943:Amino Acid Substitution / Q000187:drug effects; D000596:Amino Acids; D000818:Animals; D002352:Carrier Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D022083:Cytoplasmic Structures / Q000187:drug effects / Q000378:metabolism*; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000378:metabolism*; D020730:Guanine Nucleotide Dissociation Inhibitors; D006801:Humans; D007976:Leupeptins / Q000494:pharmacology; D050505:Mutant Proteins / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D061988:Proteasome Inhibitors; D011485:Protein Binding / Q000187:drug effects; D017434:Protein Structure, Tertiary; D021381:Protein Transport / Q000187:drug effects; D051381:Rats; D020449:Repetitive Sequences, Amino Acid; D017384:Sequence Deletion / Q000187:drug effects; D013329:Structure-Activity Relationship; D013347:Subcellular Fractions / Q000187:drug effects / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D000596:Amino Acids; D002352:Carrier Proteins; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D020730:Guanine Nucleotide Dissociation Inhibitors; D007976:Leupeptins; D050505:Mutant Proteins; D061988:Proteasome Inhibitors; C525615:GPSM1 protein, human; C498913:Gpsm1 protein, rat; C509688:INSC protein, human; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde