Molecular determinants of g protein signaling selectivity
The molecular basis of selectivity in receptor-(î protein coupling has been explored by comparing the abilities of G protein heterotrimers containing chimeric Go subunits, comprised of various regions of Ga,i, Gat and Gft?. to function ally interact with distinct subtypes of serotonin (5-HTj). adenosine A) and muscarinic acetylcholine receptors. Functional interactions with receptors expressed in Sf9 cell membranes have been assessed by examining both the ability of the G protein to induce the high affinity state of the receptor (affinity-shift activity) and the ability of the agonist occupied receptor to catalyze guanine n u cleotide exchange on the G protein (GTP binding). Data for chimeric subunits demonstrate that multiple and distinct determinants of selectivity exist for individual receptor families. Furthermore, the ability of heterotrimers incapable of functional interactions with receptors to competitively inhibit the affinity shift activity of native Gil indicates that the receptor-G protein interaction can be examined in two distinct biochemical events, binding and activation. A general low affinity interaction between receptors and G proteins exists even in the absence of functional, high affinity interactions, and multiple domains contribute to the selective recognition that results in a functional, high affinity interaction capable of initiating a cellular signal.
Graber, SG; Bae, H; Deprec, KM; Slessareva, JE; Skiba, NP; Harnm, HE
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