Structural highlights
Function[GNAI1_RAT] Guanine nucleotide-binding proteins (G proteins) are involved as modulators or transducers in various transmembrane signaling systems. The G(i) proteins are involved in hormonal regulation of adenylate cyclase: they inhibit the cyclase in response to beta-adrenergic stimuli. The inactive GDP-bound form prevents the association of RGS14 with centrosomes and is required for the translocation of RGS14 from the cytoplasm to the plasma membrane. May play a role in cell division.[1] Publication Abstract from PubMedG protein activation by G protein coupled receptors (GPCRs) is one of the critical steps for many cellular signal transduction pathways. Previously, we and other groups reported that the alpha 5 (alpha5) helix in the G protein alpha subunit plays a major role during this activation process. However, the precise signaling pathway between the alpha5 helix and the GDP binding pocket remains elusive. Here, using structural, biochemical and computational techniques, we probed different residues around the alpha5 helix for their role in signaling. Our data showed that perturbing the F336 (alpha5) residue disturbs hydrophobic interactions with the beta2-beta3 strands and alpha1 helix, leading to high basal nucleotide exchange. However, mutations in beta strands beta5 and beta6 do not perturb G protein activation. We have highlighted critical residues that leverage F336 as a relay. Conformational changes are transmitted starting from F336 via beta2-beta3/alpha1 to Switch I and the P-loop, decreasing the stability of the GDP binding pocket and triggering nucleotide release. When the alpha1 and alpha5 helices were cross-linked, inhibiting the receptor-mediated displacement of the C-terminal alpha5 helix, mutation of F336 still leads to high basal exchange. This suggests that unlike receptor mediated activation, helix 5 rotation and translocation is not necessary for GDP release from the alpha subunit. Rather, destabilization of the backdoor region of the Galpha subunit is sufficient for triggering the activation process. A conserved phenylalanine as relay between the alpha5 helix and the GDP binding region of heterotrimeric Gi protein alpha subunit.,Kaya AI, Lokits AD, Gilbert JA, Iverson TM, Meiler J, Hamm HE J Biol Chem. 2014 Jul 18. pii: jbc.M114.572875. PMID:25037222[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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