FARNESYLCYSTEINE ANALOGS INHIBIT CHEMOTACTIC PEPTIDE RECEPTOR-MEDIATED G-PROTEIN ACTIVATION IN HUMAN HL-60 GRANULOCYTE MEMBRANES

被引:53
作者
SCHEER, A [1 ]
GIERSCHIK, P [1 ]
机构
[1] GERMAN CANC RES CTR,DIV MOLEC PHARMACOL,NEUENHEIMER FELD 280-0425,W-6900 HEIDELBERG,GERMANY
关键词
G-PROTEIN; SIGNAL TRANSDUCTION; PROTEIN O-METHYLTRANSFERASE; PRENYLCYSTEINE; CHEMOTAXIS; HL-60; CELL;
D O I
10.1016/0014-5793(93)80047-X
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
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 chemotactic response of mouse macrophages. Here, we show that AFC inhibits both basal and formyl 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 formyl peptide receptor-mediated G-protein activation is also observed for S-trans,trans-farnesyl-3-thiopropionic acid, but not for N-acetyl-S-trans-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.
引用
收藏
页码:110 / 114
页数:5
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