Galpha(s) is palmitoylated at the N-terminal glycine.
Covalent lipid attachments are essential co- and post-translational modifications for signalling proteins. Galpha(s), the alpha-subunit of the heterotrimeric G protein that activates adenylyl cyclase, is known to be palmitoylated at the third N-terminal amino acid, a cysteine. Palmitoylation is involved in anchoring Galpha(s) to the membrane by increasing its intrinsic hydrophobicity. We identified by mass spectrometry a second, functionally even more important, covalent modification. It consists of another palmitoyl residue attached to the preceding glycine (Gly(2)). Palmitoylation at this position has profound consequences for levels of signal transduction. It sensitizes the cell up to 200-fold for adenylyl cyclase-stimulating agents. The inhibitory inputs mediated by Galpha(i) are downregulated to <10%. Thereby, Gly(2)-palmitoylation of Galpha(s) relieves cellular stimulation at the level of adenylyl cyclase whereas it renders the inhibitory modulation via Galpha(i) more difficult.
Kleuss
Christiane
C
Institut für Pharmakologie, Freie Universität Berlin, Thielallee 67-73, 14195 Berlin. ckleuss@zedat.fu-berlin.de
Krause
Eberhard
E
D000067956:Adenylyl Cyclase Inhibitors; D000262:Adenylyl Cyclases / Q000378:metabolism; D029742:Caenorhabditis elegans Proteins; D003545:Cysteine / Q000378:metabolism; D004789:Enzyme Activation / Q000502:physiology; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D005998:Glycine / Q000378:metabolism*; D020962:Heterotrimeric GTP-Binding Proteins / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D013058:Mass Spectrometry; D010171:Palmitoyl Coenzyme A / Q000378:metabolism*
D000067956:Adenylyl Cyclase Inhibitors; D029742:Caenorhabditis elegans Proteins; C110666:odr-3 protein, C elegans; D010171:Palmitoyl Coenzyme A; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D020962:Heterotrimeric GTP-Binding Proteins; D000262:Adenylyl Cyclases; D003545:Cysteine; D005998:Glycine