Posttranslational modification of proteins by isoprenoids in mammalian cells.
Isoprenylation is a posttranslational modification that involves the formation of thioether bonds between cysteine and isoprenyl groups derived from pyrophosphate intermediates of the cholesterol biosynthetic pathway. Numerous isoprenylated proteins have been detected in mammalian cells. Those identified include K-, N-, and H-p21ras, ras-related GTP-binding proteins such as G25K (Gp), nuclear lamin B and prelamin A, and the gamma subunits of heterotrimeric G proteins. The modified cysteine is located in the fourth position from the carboxyl terminus in every protein where this has been studied. For p21ras, the last three amino acids are subsequently removed and the exposed cysteine is carboxylmethylated. Similar processing events may occur in lamin B and G protein gamma subunits, but the proteolytic cleavage in prelamin A occurs upstream from the modified cysteine. Lamin B and p21ras are modified by C15 farnesyl groups, whereas other proteins such as the G protein gamma subunits are modified by C20 geranylgeranyl chains. Separate enzymes may catalyze these modifications. The structural features that govern the ability of particular proteins to serve as substrates for isoprenylation by C15 or C20 groups are not completely defined, but studies of the p21ras modification using purified farnesyl:protein transferase suggest that the sequence of the carboxyl-terminal tetrapeptide is important. Isoprenylation plays a critical role in promoting the association of p21ras and the lamins with the cell membrane and nuclear envelope, respectively. Future studies of the role of isoprenylation in the localization and function of ras-related GTP-binding proteins and signal-transducing G proteins should provide valuable new insight into the link between isoprenoid biosynthesis and cell growth.
Maltese
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Weis Center for Research, Geisinger Clinic, Danville, Pennsylvania 17822.
D000595:Amino Acid Sequence; D000818:Animals; D002453:Cell Cycle; D019204:GTP-Binding Proteins / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D034921:Lamin Type B; D034882:Lamins; D008798:Mevalonic Acid / Q000378:metabolism; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000737:chemistry / Q000378:metabolism; D015689:Oncogene Protein p21(ras) / Q000737:chemistry / Q000378:metabolism; D011106:Polyisoprenyl Phosphates / Q000378:metabolism*; D011499:Protein Processing, Post-Translational; D011506:Proteins / Q000737:chemistry / Q000378:metabolism
D034921:Lamin Type B; D034882:Lamins; D009687:Nuclear Proteins; D011106:Polyisoprenyl Phosphates; D011506:Proteins; D019204:GTP-Binding Proteins; D015689:Oncogene Protein p21(ras); D008798:Mevalonic Acid