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SHR Neuro Krebs Kardio Lipid Stoffw Microb
Kostenis, E; Martini, L; Ellis, J; Waldhoer, M; Heydorn, A; Rosenkilde, MM; Norregaard, PK; Jorgensen, R; Whistler, JL; Milligan, G.
A highly conserved glycine within linker I and the extreme C terminus of G protein alpha subunits interact cooperatively in switching G protein-coupled receptor-to-effector specificity.
J PHARMACOL EXP THER. 2005; 313: 78-87.
Doi: 10.1124/jpet.104.080424
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- Co-Autor*innen der Med Uni Graz
- Waldhoer Maria
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- Abstract:
- Numerous studies have attested to the importance of the extreme C terminus of G protein alpha subunits in determining their selectivity of receptor recognition. We have previously reported that a highly conserved glycine residue within linker I is important for constraining the fidelity of receptor recognition by Galpha(q) proteins. Herein, we explored whether both modules (linker I and extreme C terminus) interact cooperatively in switching G protein-coupled receptor (GPCR)-to-effector specificity and created as models mutant Galpha(q) proteins in which glycine was replaced with various amino acids and the C-terminal five Galpha(q) residues with the corresponding Galpha(i) or Galpha(s) sequence. Coupling properties of the mutated Galpha(q) proteins were determined after coexpression with a panel of 13 G(i)-and G(s) -selective receptors and compared with those of Galpha proteins modified in only one module. Galpha proteins modified in both modules are significantly more efficacious in channeling non-G(q) -selective receptors to G(q)-mediated signaling events compare with those containing each module alone. Additive effects of both modules were observed even if individual modules lacked an effect on GPCR-to-effector specificity. Dually modified Galpha proteins were also superior in conferring high-affinity agonist sites onto a coexpressed GPCR in the absence, but not in the presence, of guanine nucleotides. Together, our data suggest that receptor-G protein coupling selectivity involves cooperative interactions between the extreme C terminus and linker I of Galpha proteins and that distinct determinants of selectivity exist for individual receptors.
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- Conserved Sequence - metabolism
- DNA - biosynthesis
- Enzyme-Linked Immunosorbent Assay - biosynthesis
- GTP-Binding Protein alpha Subunits - metabolism
- Glycine - metabolism
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- Molecular Sequence Data - metabolism
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