Farnesylcysteine analogues inhibit chemotactic peptide receptor‐mediated G‐protein activation in human HL‐60 granulocyte membranes

FEBS Letters

Scheer, Alexander¹  Gierschik, Peter¹ 

[1] Molecular Pharmacology Division, German Cancer Research Center, Heidelberg, Germany

关键词: G-protein;    Signal transduction;    Protein O-Methyltransferase;    Prenylcysteine;    Chemotaxis;    HL-60 cell;    G-proteins;    signal-transducing heterotrimeric guanine nucleotide-binding protein;    GTP[S];    guanosine 5'-O-(3-thiotriphos-phate);    fMet-Leu-Phe;    W-formyl-methionyl-leucyl-phenylalanine;    AFC;    N-acetyl-S-trans;    trans-farnesyl-l-cysteine;    AGC;    N-acetyl-S-trans-geranyl-l-cysteine;    FTP;    S-trans;    trans-farnesyl-3-thiopropionic acid;    AFCMe;    N-acetyl-S-trans;    trans-farnesyl-l-cysteine methyl ester;   

DOI  :  10.1016/0014-5793(93)80047-X

学科分类：生物化学/生物物理

来源: John Wiley & Sons Ltd.

【 摘 要 】

Analogues of S-prenylated cysteine like N-acetyl-S-trans,trans-farnesyl-l-cysteine (AFC) have previously been shown to inhibit the carboxyl methylation of proteins carrying a C-terminal S-prenylated cysteine residue and to block the endotoxin-activated serum-elicited ehemotactic response of mouse macrophages. Here, we show that AFC inhibits both basal and fonnyl peptide receptor-stimulated binding of guanosine 5'-O-(3-thiotriphosphate) (GTP[S]) to and hydrolysis of GTP by membranes of myeloid differentiated HL-60 granulocytes. Receptor-stimulated GTP[S] binding and GTP hydrolysis are more sensitive to AFC inhibition than basal G-protein functions. Inhibition of fonnyl peptide receptor-mediated G-protein activation is also observed for S-trans,trans-famesyl-3-thiopropionic acid, but not for N-acetyl-S-tarns-geranyl-l-cysteine, N-acetyl-l-cysteine, or the methyl ester of AFC, suggesting that the farnesyl moiety and the carboxyl group, but not the peptide bond of AFC are required for inhibition. The observations that exogeneous S-adenosyl-l-methionine is apparently not required for and S-adenosyl-l-homocysteine does not attenuate the inhibitory action of AFC raise the distinct possibility that AFC inhibits receptor-mediated G-protein interaction by a mechanism other than inhibition of protein carboxyl methylation.

【 授权许可】

Unknown