A G-protein gamma subunit mimic is a general antagonist of prion propagation in Saccharomyces cerevisiae.
The Gpg1 protein is a Ggamma subunit mimic implicated in the G-protein glucose-signaling pathway in Saccharomyces cerevisiae, and its function is largely unknown. Here we report that Gpg1 blocks the maintenance of [PSI(+)], an aggregated prion form of the translation termination factor Sup35. Although the GPG1 gene is normally not expressed, over-expression of GPG1 inhibits propagation of not only [PSI(+)] but also [PIN(+)], [URE3] prions, and the toxic polyglutamine aggregate in S. cerevisiae. Over-expression of Gpg1 does not affect expression and activity of Hsp104, a protein-remodeling factor required for prion propagation, showing that Gpg1 does not target Hsp104 directly. Nevertheless, prion elimination by Gpg1 is weakened by over-expression of Hsp104. Importantly, Gpg1 protein is prone to self-aggregate and transiently colocalized with Sup35NM-prion aggregates when expressed in [PSI(+)] cells. Genetic selection and characterization of loss-of-activity gpg1 mutations revealed that multiple mutations on the hydrophobic one-side surface of predicted alpha-helices of the Gpg1 protein hampered the activity. Prion elimination by Gpg1 is unaffected in the gpa2Delta and gpb1Delta strains lacking the supposed physiological G-protein partners of Gpg1. These findings suggest a general inhibitory interaction of the Gpg1 protein with other transmissible and nontransmissible amyloids, resulting in prion elimination. Assuming the ability of Gpg1 to form G-protein heterotrimeric complexes, Gpg1 is likely to play a versatile function of reversing the prion state and modulating the G-protein signaling pathway.
Ishiwata
Masao
M
Department of Basic Medical Sciences, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo 108-8639, Japan.
Kurahashi
Hiroshi
H
Nakamura
Yoshikazu
Y
D044385:GTP-Binding Protein alpha Subunits / Q000502:physiology; D044387:GTP-Binding Protein beta Subunits / Q000502:physiology; D044388:GTP-Binding Protein gamma Subunits / Q000502:physiology*; D006360:Heat-Shock Proteins / Q000502:physiology; D009154:Mutation; D011328:Prions / Q000037:antagonists & inhibitors*; D012441:Saccharomyces cerevisiae / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000502:physiology
D044385:GTP-Binding Protein alpha Subunits; D044387:GTP-Binding Protein beta Subunits; D044388:GTP-Binding Protein gamma Subunits; D006360:Heat-Shock Proteins; D011328:Prions; D029701:Saccharomyces cerevisiae Proteins; C070972:HsP104 protein, S cerevisiae