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The tandem CCCH zinc finger protein tristetraprolin and its relevance to cytokine mRNA turnover and arthritis.

Carrick DM, Lai WS, Blackshear PJ - Arthritis Res. Ther. (2004)

Bottom Line: The syndrome seemed to be due predominantly to excess circulating tumor necrosis factor-alpha (TNF-alpha), resulting from the increased stability of the TNF-alpha mRNA and subsequent higher rates of secretion of the cytokine.Recent structural data on the characteristics of the complex between RNA and one of the TTP-related proteins are reviewed, and used to model the TTP-RNA binding complex.The TTP pathway of TNF-alpha and GM-CSF mRNA degradation is a possible novel target for anti-TNF-alpha therapies for rheumatoid arthritis, and also for other conditions proven to respond to anti-TNF-alpha therapy.

View Article: PubMed Central - HTML - PubMed

Affiliation: Office of Clinical Research, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, USA.

ABSTRACT
Tristetraprolin (TTP) is the best-studied member of a small family of three proteins in humans that is characterized by a tandem CCCH zinc finger (TZF) domain with highly conserved sequences and spacing. Although initially discovered as a gene that could be induced rapidly and transiently by the stimulation of fibroblasts with growth factors and mitogens, it is now known that TTP can bind to AU-rich elements in mRNA, leading to the removal of the poly(A) tail from that mRNA and increased rates of mRNA turnover. This activity was discovered after TTP-deficient mice were created and found to have a systemic inflammatory syndrome with severe polyarticular arthritis and autoimmunity, as well as medullary and extramedullary myeloid hyperplasia. The syndrome seemed to be due predominantly to excess circulating tumor necrosis factor-alpha (TNF-alpha), resulting from the increased stability of the TNF-alpha mRNA and subsequent higher rates of secretion of the cytokine. The myeloid hyperplasia might be due in part to increased stability of granulocyte-macrophage colony-stimulating factor (GM-CSF). This review highlights briefly the characteristics of the TTP-deficiency syndrome in mice and its possible genetic modifiers, as well as recent data on the characteristics of the TTP-binding site in the TNF-alpha and GM-CSF mRNAs. Recent structural data on the characteristics of the complex between RNA and one of the TTP-related proteins are reviewed, and used to model the TTP-RNA binding complex. We review the current knowledge of TTP sequence variants in humans and discuss the possible contributions of the TTP-related proteins in mouse physiology and in human monocytes. The TTP pathway of TNF-alpha and GM-CSF mRNA degradation is a possible novel target for anti-TNF-alpha therapies for rheumatoid arthritis, and also for other conditions proven to respond to anti-TNF-alpha therapy.

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Proposed structure of the human tristetraprolin (TTP) tandem zinc finger domain in complex with the TTP-binding site 5'-UUAUUUAUU-3'. This proposed structure was modeled on the original nuclear magnetic resonance structure described by [32], using their pdb coordinates and the Swiss-Model program. The RNA oligonucleotide is shown in magenta, with the 5' and 3' ends indicated, along with the key residues A3, U5, and A7. The peptide is shown as a surface structure, with the buried zinc residues highlighted and the amino-terminal (N-term.) and carboxy-terminal (C-term.) ends of the peptide shown by arrows. The dark blue residues represent amino acids that are identical between human TTP and the ZFP36L2 (TIS11D) protein used in the original structure. The other colors represent progressively greater amino acid differences between the two proteins, ranging from minimally different (aquamarine, upper right), through green, yellow, and orange, with orange representing the most marked amino acid differences.
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Figure 4: Proposed structure of the human tristetraprolin (TTP) tandem zinc finger domain in complex with the TTP-binding site 5'-UUAUUUAUU-3'. This proposed structure was modeled on the original nuclear magnetic resonance structure described by [32], using their pdb coordinates and the Swiss-Model program. The RNA oligonucleotide is shown in magenta, with the 5' and 3' ends indicated, along with the key residues A3, U5, and A7. The peptide is shown as a surface structure, with the buried zinc residues highlighted and the amino-terminal (N-term.) and carboxy-terminal (C-term.) ends of the peptide shown by arrows. The dark blue residues represent amino acids that are identical between human TTP and the ZFP36L2 (TIS11D) protein used in the original structure. The other colors represent progressively greater amino acid differences between the two proteins, ranging from minimally different (aquamarine, upper right), through green, yellow, and orange, with orange representing the most marked amino acid differences.

Mentions: We have taken the coordinates of the ZFP36L2 TZF domain complex and modeled the structure of the interaction of the human TTP TZF peptide with the RNA nonamer, using the Swiss-Model programs [33,34]. A surface depiction of this model is shown in Fig. 4. It should be emphasized that this is a model based on the published ZFP36L2 TZF domain structure [32], but the two sequences are so closely related that it seems likely to be a fairly close approximation of the final TTP TZF domain structure in complex with its RNA target.


The tandem CCCH zinc finger protein tristetraprolin and its relevance to cytokine mRNA turnover and arthritis.

Carrick DM, Lai WS, Blackshear PJ - Arthritis Res. Ther. (2004)

Proposed structure of the human tristetraprolin (TTP) tandem zinc finger domain in complex with the TTP-binding site 5'-UUAUUUAUU-3'. This proposed structure was modeled on the original nuclear magnetic resonance structure described by [32], using their pdb coordinates and the Swiss-Model program. The RNA oligonucleotide is shown in magenta, with the 5' and 3' ends indicated, along with the key residues A3, U5, and A7. The peptide is shown as a surface structure, with the buried zinc residues highlighted and the amino-terminal (N-term.) and carboxy-terminal (C-term.) ends of the peptide shown by arrows. The dark blue residues represent amino acids that are identical between human TTP and the ZFP36L2 (TIS11D) protein used in the original structure. The other colors represent progressively greater amino acid differences between the two proteins, ranging from minimally different (aquamarine, upper right), through green, yellow, and orange, with orange representing the most marked amino acid differences.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC1064869&req=5

Figure 4: Proposed structure of the human tristetraprolin (TTP) tandem zinc finger domain in complex with the TTP-binding site 5'-UUAUUUAUU-3'. This proposed structure was modeled on the original nuclear magnetic resonance structure described by [32], using their pdb coordinates and the Swiss-Model program. The RNA oligonucleotide is shown in magenta, with the 5' and 3' ends indicated, along with the key residues A3, U5, and A7. The peptide is shown as a surface structure, with the buried zinc residues highlighted and the amino-terminal (N-term.) and carboxy-terminal (C-term.) ends of the peptide shown by arrows. The dark blue residues represent amino acids that are identical between human TTP and the ZFP36L2 (TIS11D) protein used in the original structure. The other colors represent progressively greater amino acid differences between the two proteins, ranging from minimally different (aquamarine, upper right), through green, yellow, and orange, with orange representing the most marked amino acid differences.
Mentions: We have taken the coordinates of the ZFP36L2 TZF domain complex and modeled the structure of the interaction of the human TTP TZF peptide with the RNA nonamer, using the Swiss-Model programs [33,34]. A surface depiction of this model is shown in Fig. 4. It should be emphasized that this is a model based on the published ZFP36L2 TZF domain structure [32], but the two sequences are so closely related that it seems likely to be a fairly close approximation of the final TTP TZF domain structure in complex with its RNA target.

Bottom Line: The syndrome seemed to be due predominantly to excess circulating tumor necrosis factor-alpha (TNF-alpha), resulting from the increased stability of the TNF-alpha mRNA and subsequent higher rates of secretion of the cytokine.Recent structural data on the characteristics of the complex between RNA and one of the TTP-related proteins are reviewed, and used to model the TTP-RNA binding complex.The TTP pathway of TNF-alpha and GM-CSF mRNA degradation is a possible novel target for anti-TNF-alpha therapies for rheumatoid arthritis, and also for other conditions proven to respond to anti-TNF-alpha therapy.

View Article: PubMed Central - HTML - PubMed

Affiliation: Office of Clinical Research, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, USA.

ABSTRACT
Tristetraprolin (TTP) is the best-studied member of a small family of three proteins in humans that is characterized by a tandem CCCH zinc finger (TZF) domain with highly conserved sequences and spacing. Although initially discovered as a gene that could be induced rapidly and transiently by the stimulation of fibroblasts with growth factors and mitogens, it is now known that TTP can bind to AU-rich elements in mRNA, leading to the removal of the poly(A) tail from that mRNA and increased rates of mRNA turnover. This activity was discovered after TTP-deficient mice were created and found to have a systemic inflammatory syndrome with severe polyarticular arthritis and autoimmunity, as well as medullary and extramedullary myeloid hyperplasia. The syndrome seemed to be due predominantly to excess circulating tumor necrosis factor-alpha (TNF-alpha), resulting from the increased stability of the TNF-alpha mRNA and subsequent higher rates of secretion of the cytokine. The myeloid hyperplasia might be due in part to increased stability of granulocyte-macrophage colony-stimulating factor (GM-CSF). This review highlights briefly the characteristics of the TTP-deficiency syndrome in mice and its possible genetic modifiers, as well as recent data on the characteristics of the TTP-binding site in the TNF-alpha and GM-CSF mRNAs. Recent structural data on the characteristics of the complex between RNA and one of the TTP-related proteins are reviewed, and used to model the TTP-RNA binding complex. We review the current knowledge of TTP sequence variants in humans and discuss the possible contributions of the TTP-related proteins in mouse physiology and in human monocytes. The TTP pathway of TNF-alpha and GM-CSF mRNA degradation is a possible novel target for anti-TNF-alpha therapies for rheumatoid arthritis, and also for other conditions proven to respond to anti-TNF-alpha therapy.

Show MeSH
Related in: MedlinePlus