C-terminal lipidation is essential for proper function of many signal transduction proteins (such as Ras) . This modification is catalyzed by protein farnesyltransferase (FTase). Click here for a tour of the FTase enzyme . Proteins that act as substrates for the FTase have a sequence known as a CAAX box. The X refers to the C-terminus, each A refers to an aliphatic amino acid, and the C refers to a cysteine residue. FTase catalyzes farnesylation using farnesyl diphosphate (FPP) as the prenyl chain donor. Formation of a thioether linkage to the cysteine residue of the CAAX box modifies the substrate protein. FTase consists of two domains: The Alpha Subunit The alpha subunit is a helical hairpin domain that has a crescent shape. The helices are folded into seven pairs, which in turn form a series of antiparallel right-handed coiled coils. The crescent shape results from the helical hairpins being arranged in a double-layered superhelix. Each helix is parallel to the other helices in the same layer and antiparallel to the helices in the adjacent layer. The alpha subunit envelops much of the beta subunit. The Beta Subunit The beta subunit consists of 12 helices that fold to form an alpha-alpha barrel. This barrel has two layers. The 6 helices that line the inside of the barrel are all parallel to each other. These helices are antiparallel to the 6 helices that form the outer layer of the barrel. While one end of the barrel is open to solvent the other end is covered by a loop. Both the protein substrate and FPP binding sites are located on the beta subunit. The binding sites are located in two clefts. These clefts form the active site. Their intersection is marked by a zinc ion. One cleft, the substrate binding site, is formed by three loops. Lys164 in the alpha subunit, and Arg291, Lys294, Arg300, His248, and Tyr361 bind the substrate. The other cleft, the FPP binding site, is located in the alpha-alpha barrel's central cavity. Numerous aromatic residues line this cleft including four tryptophan residues, two phenylalanine residues, and 5 tyrosine residues. The substrate's cysteine that will be farnesylated is close to the zinc ion and the alpha phosphate of the FPP. The oncogenic variants of ras require farnesylation to transform their cells into tumorigenic states. Since FTase catalyzes this farnesylation, researchers are targeting FTase as a potential chemotherapeutic agent. Current studies have shown that inhibition of FTase, in mice, has resulted in tumor regression. For more information consult: Park, H.W., et al. (1997) Science 275: 1800-1804. You may wish to manipulate this image yourself: Click and hold the left mouse button to rotate the image about the x and y axes. Rotate about the z axis by pressing the shift key and right mouse button together. The image may be translated along the x and y axes by pressing control and the right mouse button. By pressing shift and the left mouse button together, you may zoom the image in or out. Clicking the right mouse button on the image gives a menu which offers several choices, including spinning the image and changing the appearance and color of the molecule.
Proteins that act as substrates for the FTase have a sequence known as a CAAX box. The X refers to the C-terminus, each A refers to an aliphatic amino acid, and the C refers to a cysteine residue. FTase catalyzes farnesylation using farnesyl diphosphate (FPP) as the prenyl chain donor. Formation of a thioether linkage to the cysteine residue of the CAAX box modifies the substrate protein. FTase consists of two domains: The Alpha Subunit The alpha subunit is a helical hairpin domain that has a crescent shape. The helices are folded into seven pairs, which in turn form a series of antiparallel right-handed coiled coils. The crescent shape results from the helical hairpins being arranged in a double-layered superhelix. Each helix is parallel to the other helices in the same layer and antiparallel to the helices in the adjacent layer. The alpha subunit envelops much of the beta subunit. The Beta Subunit The beta subunit consists of 12 helices that fold to form an alpha-alpha barrel. This barrel has two layers. The 6 helices that line the inside of the barrel are all parallel to each other. These helices are antiparallel to the 6 helices that form the outer layer of the barrel. While one end of the barrel is open to solvent the other end is covered by a loop. Both the protein substrate and FPP binding sites are located on the beta subunit. The binding sites are located in two clefts. These clefts form the active site. Their intersection is marked by a zinc ion. One cleft, the substrate binding site, is formed by three loops. Lys164 in the alpha subunit, and Arg291, Lys294, Arg300, His248, and Tyr361 bind the substrate. The other cleft, the FPP binding site, is located in the alpha-alpha barrel's central cavity. Numerous aromatic residues line this cleft including four tryptophan residues, two phenylalanine residues, and 5 tyrosine residues. The substrate's cysteine that will be farnesylated is close to the zinc ion and the alpha phosphate of the FPP. The oncogenic variants of ras require farnesylation to transform their cells into tumorigenic states. Since FTase catalyzes this farnesylation, researchers are targeting FTase as a potential chemotherapeutic agent. Current studies have shown that inhibition of FTase, in mice, has resulted in tumor regression. For more information consult: Park, H.W., et al. (1997) Science 275: 1800-1804. You may wish to manipulate this image yourself: Click and hold the left mouse button to rotate the image about the x and y axes. Rotate about the z axis by pressing the shift key and right mouse button together. The image may be translated along the x and y axes by pressing control and the right mouse button. By pressing shift and the left mouse button together, you may zoom the image in or out. Clicking the right mouse button on the image gives a menu which offers several choices, including spinning the image and changing the appearance and color of the molecule.
FTase consists of two domains: The Alpha Subunit The alpha subunit is a helical hairpin domain that has a crescent shape. The helices are folded into seven pairs, which in turn form a series of antiparallel right-handed coiled coils. The crescent shape results from the helical hairpins being arranged in a double-layered superhelix. Each helix is parallel to the other helices in the same layer and antiparallel to the helices in the adjacent layer. The alpha subunit envelops much of the beta subunit. The Beta Subunit The beta subunit consists of 12 helices that fold to form an alpha-alpha barrel. This barrel has two layers. The 6 helices that line the inside of the barrel are all parallel to each other. These helices are antiparallel to the 6 helices that form the outer layer of the barrel. While one end of the barrel is open to solvent the other end is covered by a loop. Both the protein substrate and FPP binding sites are located on the beta subunit. The binding sites are located in two clefts. These clefts form the active site. Their intersection is marked by a zinc ion. One cleft, the substrate binding site, is formed by three loops. Lys164 in the alpha subunit, and Arg291, Lys294, Arg300, His248, and Tyr361 bind the substrate. The other cleft, the FPP binding site, is located in the alpha-alpha barrel's central cavity. Numerous aromatic residues line this cleft including four tryptophan residues, two phenylalanine residues, and 5 tyrosine residues. The substrate's cysteine that will be farnesylated is close to the zinc ion and the alpha phosphate of the FPP. The oncogenic variants of ras require farnesylation to transform their cells into tumorigenic states. Since FTase catalyzes this farnesylation, researchers are targeting FTase as a potential chemotherapeutic agent. Current studies have shown that inhibition of FTase, in mice, has resulted in tumor regression. For more information consult: Park, H.W., et al. (1997) Science 275: 1800-1804. You may wish to manipulate this image yourself: Click and hold the left mouse button to rotate the image about the x and y axes. Rotate about the z axis by pressing the shift key and right mouse button together. The image may be translated along the x and y axes by pressing control and the right mouse button. By pressing shift and the left mouse button together, you may zoom the image in or out. Clicking the right mouse button on the image gives a menu which offers several choices, including spinning the image and changing the appearance and color of the molecule.
The Alpha Subunit The alpha subunit is a helical hairpin domain that has a crescent shape. The helices are folded into seven pairs, which in turn form a series of antiparallel right-handed coiled coils. The crescent shape results from the helical hairpins being arranged in a double-layered superhelix. Each helix is parallel to the other helices in the same layer and antiparallel to the helices in the adjacent layer. The alpha subunit envelops much of the beta subunit. The Beta Subunit The beta subunit consists of 12 helices that fold to form an alpha-alpha barrel. This barrel has two layers. The 6 helices that line the inside of the barrel are all parallel to each other. These helices are antiparallel to the 6 helices that form the outer layer of the barrel. While one end of the barrel is open to solvent the other end is covered by a loop. Both the protein substrate and FPP binding sites are located on the beta subunit. The binding sites are located in two clefts. These clefts form the active site. Their intersection is marked by a zinc ion. One cleft, the substrate binding site, is formed by three loops. Lys164 in the alpha subunit, and Arg291, Lys294, Arg300, His248, and Tyr361 bind the substrate. The other cleft, the FPP binding site, is located in the alpha-alpha barrel's central cavity. Numerous aromatic residues line this cleft including four tryptophan residues, two phenylalanine residues, and 5 tyrosine residues. The substrate's cysteine that will be farnesylated is close to the zinc ion and the alpha phosphate of the FPP. The oncogenic variants of ras require farnesylation to transform their cells into tumorigenic states. Since FTase catalyzes this farnesylation, researchers are targeting FTase as a potential chemotherapeutic agent. Current studies have shown that inhibition of FTase, in mice, has resulted in tumor regression. For more information consult: Park, H.W., et al. (1997) Science 275: 1800-1804. You may wish to manipulate this image yourself: Click and hold the left mouse button to rotate the image about the x and y axes. Rotate about the z axis by pressing the shift key and right mouse button together. The image may be translated along the x and y axes by pressing control and the right mouse button. By pressing shift and the left mouse button together, you may zoom the image in or out. Clicking the right mouse button on the image gives a menu which offers several choices, including spinning the image and changing the appearance and color of the molecule.
The crescent shape results from the helical hairpins being arranged in a double-layered superhelix. Each helix is parallel to the other helices in the same layer and antiparallel to the helices in the adjacent layer. The alpha subunit envelops much of the beta subunit. The Beta Subunit The beta subunit consists of 12 helices that fold to form an alpha-alpha barrel. This barrel has two layers. The 6 helices that line the inside of the barrel are all parallel to each other. These helices are antiparallel to the 6 helices that form the outer layer of the barrel. While one end of the barrel is open to solvent the other end is covered by a loop. Both the protein substrate and FPP binding sites are located on the beta subunit. The binding sites are located in two clefts. These clefts form the active site. Their intersection is marked by a zinc ion. One cleft, the substrate binding site, is formed by three loops. Lys164 in the alpha subunit, and Arg291, Lys294, Arg300, His248, and Tyr361 bind the substrate. The other cleft, the FPP binding site, is located in the alpha-alpha barrel's central cavity. Numerous aromatic residues line this cleft including four tryptophan residues, two phenylalanine residues, and 5 tyrosine residues. The substrate's cysteine that will be farnesylated is close to the zinc ion and the alpha phosphate of the FPP. The oncogenic variants of ras require farnesylation to transform their cells into tumorigenic states. Since FTase catalyzes this farnesylation, researchers are targeting FTase as a potential chemotherapeutic agent. Current studies have shown that inhibition of FTase, in mice, has resulted in tumor regression. For more information consult: Park, H.W., et al. (1997) Science 275: 1800-1804. You may wish to manipulate this image yourself: Click and hold the left mouse button to rotate the image about the x and y axes. Rotate about the z axis by pressing the shift key and right mouse button together. The image may be translated along the x and y axes by pressing control and the right mouse button. By pressing shift and the left mouse button together, you may zoom the image in or out. Clicking the right mouse button on the image gives a menu which offers several choices, including spinning the image and changing the appearance and color of the molecule.
The Beta Subunit The beta subunit consists of 12 helices that fold to form an alpha-alpha barrel. This barrel has two layers. The 6 helices that line the inside of the barrel are all parallel to each other. These helices are antiparallel to the 6 helices that form the outer layer of the barrel. While one end of the barrel is open to solvent the other end is covered by a loop. Both the protein substrate and FPP binding sites are located on the beta subunit. The binding sites are located in two clefts. These clefts form the active site. Their intersection is marked by a zinc ion. One cleft, the substrate binding site, is formed by three loops. Lys164 in the alpha subunit, and Arg291, Lys294, Arg300, His248, and Tyr361 bind the substrate. The other cleft, the FPP binding site, is located in the alpha-alpha barrel's central cavity. Numerous aromatic residues line this cleft including four tryptophan residues, two phenylalanine residues, and 5 tyrosine residues. The substrate's cysteine that will be farnesylated is close to the zinc ion and the alpha phosphate of the FPP. The oncogenic variants of ras require farnesylation to transform their cells into tumorigenic states. Since FTase catalyzes this farnesylation, researchers are targeting FTase as a potential chemotherapeutic agent. Current studies have shown that inhibition of FTase, in mice, has resulted in tumor regression. For more information consult: Park, H.W., et al. (1997) Science 275: 1800-1804. You may wish to manipulate this image yourself: Click and hold the left mouse button to rotate the image about the x and y axes. Rotate about the z axis by pressing the shift key and right mouse button together. The image may be translated along the x and y axes by pressing control and the right mouse button. By pressing shift and the left mouse button together, you may zoom the image in or out. Clicking the right mouse button on the image gives a menu which offers several choices, including spinning the image and changing the appearance and color of the molecule.
Both the protein substrate and FPP binding sites are located on the beta subunit. The binding sites are located in two clefts. These clefts form the active site. Their intersection is marked by a zinc ion. One cleft, the substrate binding site, is formed by three loops. Lys164 in the alpha subunit, and Arg291, Lys294, Arg300, His248, and Tyr361 bind the substrate. The other cleft, the FPP binding site, is located in the alpha-alpha barrel's central cavity. Numerous aromatic residues line this cleft including four tryptophan residues, two phenylalanine residues, and 5 tyrosine residues. The substrate's cysteine that will be farnesylated is close to the zinc ion and the alpha phosphate of the FPP. The oncogenic variants of ras require farnesylation to transform their cells into tumorigenic states. Since FTase catalyzes this farnesylation, researchers are targeting FTase as a potential chemotherapeutic agent. Current studies have shown that inhibition of FTase, in mice, has resulted in tumor regression. For more information consult: Park, H.W., et al. (1997) Science 275: 1800-1804. You may wish to manipulate this image yourself: Click and hold the left mouse button to rotate the image about the x and y axes. Rotate about the z axis by pressing the shift key and right mouse button together. The image may be translated along the x and y axes by pressing control and the right mouse button. By pressing shift and the left mouse button together, you may zoom the image in or out. Clicking the right mouse button on the image gives a menu which offers several choices, including spinning the image and changing the appearance and color of the molecule.
One cleft, the substrate binding site, is formed by three loops. Lys164 in the alpha subunit, and Arg291, Lys294, Arg300, His248, and Tyr361 bind the substrate. The other cleft, the FPP binding site, is located in the alpha-alpha barrel's central cavity. Numerous aromatic residues line this cleft including four tryptophan residues, two phenylalanine residues, and 5 tyrosine residues. The substrate's cysteine that will be farnesylated is close to the zinc ion and the alpha phosphate of the FPP. The oncogenic variants of ras require farnesylation to transform their cells into tumorigenic states. Since FTase catalyzes this farnesylation, researchers are targeting FTase as a potential chemotherapeutic agent. Current studies have shown that inhibition of FTase, in mice, has resulted in tumor regression. For more information consult: Park, H.W., et al. (1997) Science 275: 1800-1804. You may wish to manipulate this image yourself: Click and hold the left mouse button to rotate the image about the x and y axes. Rotate about the z axis by pressing the shift key and right mouse button together. The image may be translated along the x and y axes by pressing control and the right mouse button. By pressing shift and the left mouse button together, you may zoom the image in or out. Clicking the right mouse button on the image gives a menu which offers several choices, including spinning the image and changing the appearance and color of the molecule.
The other cleft, the FPP binding site, is located in the alpha-alpha barrel's central cavity. Numerous aromatic residues line this cleft including four tryptophan residues, two phenylalanine residues, and 5 tyrosine residues. The substrate's cysteine that will be farnesylated is close to the zinc ion and the alpha phosphate of the FPP. The oncogenic variants of ras require farnesylation to transform their cells into tumorigenic states. Since FTase catalyzes this farnesylation, researchers are targeting FTase as a potential chemotherapeutic agent. Current studies have shown that inhibition of FTase, in mice, has resulted in tumor regression. For more information consult: Park, H.W., et al. (1997) Science 275: 1800-1804. You may wish to manipulate this image yourself: Click and hold the left mouse button to rotate the image about the x and y axes. Rotate about the z axis by pressing the shift key and right mouse button together. The image may be translated along the x and y axes by pressing control and the right mouse button. By pressing shift and the left mouse button together, you may zoom the image in or out. Clicking the right mouse button on the image gives a menu which offers several choices, including spinning the image and changing the appearance and color of the molecule.
The substrate's cysteine that will be farnesylated is close to the zinc ion and the alpha phosphate of the FPP.
The oncogenic variants of ras require farnesylation to transform their cells into tumorigenic states. Since FTase catalyzes this farnesylation, researchers are targeting FTase as a potential chemotherapeutic agent. Current studies have shown that inhibition of FTase, in mice, has resulted in tumor regression.
For more information consult: Park, H.W., et al. (1997) Science 275: 1800-1804.
You may wish to manipulate this image yourself: