Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 282, Issue 27, Pages 19938-19947Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M700396200
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Funding
- NIGMS NIH HHS [GM053536, GM060286] Funding Source: Medline
- NIMH NIH HHS [MH55391] Funding Source: Medline
- NINDS NIH HHS [NS24821] Funding Source: Medline
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Accumulating evidence suggests that heterotrimeric G protein activation may not require G protein subunit dissociation. Results presented here provide evidence for a subunit dissociation-independent mechanism for G protein activation by a receptor-independent activator of G protein signaling, AGS8. AGS8 is a member of the AGS group III family of AGS proteins thought to activate G protein signaling primarily through interactions with G beta gamma subunits. Results are presented demonstrating that AGS8 binds to the effector and alpha subunit binding hot spot on G beta gamma yet does not interfere with G alpha subunit binding to G beta gamma or phospholipase C beta 2 activation. AGS8 stimulates activation of phospholipase C beta 2 by heterotrimeric G alpha beta gamma and forms a quaternary complex with G alpha(i1), G beta(1)gamma(2), and phospholipase C beta 2. AGS8 rescued phospholipase C beta binding and regulation by an inactive beta subunit with a mutation in the hot spot (beta(1)(W99A)gamma(2)) that normally prevents binding and activation of phospholipase C beta 2. This demonstrates that, in the presence of AGS8, the hot spot is not used for G beta gamma interactions with phospholipase C beta 2. Mutation of an alternate binding site for phospholipase C beta 2 in the amino- terminal coiled- coil region of G beta gamma prevented AGS8- dependent phospholipase C binding and activation. These data implicate a mechanism for AGS8, and potentially other G beta gamma binding proteins, for directing G beta gamma signaling through alternative effector activation sites on G beta gamma in the absence of subunit dissociation.
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