G? identity dictates efficacy of G?? signaling and macrophage migration.

ABSTRACT: G protein ?? subunit (G??) is a major signal transducer and controls processes ranging from cell migration to gene transcription. Despite having significant subtype heterogeneity and exhibiting diverse cell- and tissue-specific expression levels, G?? is often considered a unified signaling entity with a defined functionality. However, the molecular and mechanistic basis of G??'s signaling specificity is unknown. Here, we demonstrate that G? subunits, bearing the sole plasma membrane (PM)-anchoring motif, control the PM affinity of G?? and thereby differentially modulate G?? effector signaling in a G?-specific manner. Both G?? signaling activity and the migration rate of macrophages are strongly dependent on the PM affinity of G?. We also found that the type of C-terminal prenylation and five to six pre-CaaX motif residues at the PM-interacting region of G? control the PM affinity of G??. We further show that the overall PM affinity of the G?? pool of a cell type is a strong predictor of its G?? signaling-activation efficacy. A kinetic model encompassing multiple G? types and parameterized for empirical G?? behaviors not only recapitulated experimentally observed signaling of G??, but also suggested a G?-dependent, active-inactive conformational switch for the PM-bound G??, regulating effector signaling. Overall, our results unveil crucial aspects of signaling and cell migration regulation by G? type-specific PM affinities of G??.

SUBMITTER: Senarath K 

PROVIDER: S-EPMC5827438 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature