Functional and structural properties of stannin: Roles in cellular growth, selective toxicity, and mitochondrial responses to injury

M. L. Billingsley, J. Yun, B. E. Reese, C. E. Davidson, B. A. Buck-Koehntop, G. Veglia

Research output: Contribution to journalReview article

36 Citations (Scopus)

Abstract

Stannin (Snn) was discovered using subtractive hybridization methodology designed to find gene products related to selective organotin toxicity and apoptosis. The cDNAs for Snn were first isolated from brain tissues sensitive to trimethyltin, and were subsequently used to localize, characterize, and identify genomic DNA, and other gene products of Snn. Snn is a highly conserved, 88 amino acid protein found primarily in vertebrates. There is a minor divergence in the C-terminal sequence between amphibians and primates, but a nearly complete conservation of the first 60 residues in all vertebrates sequenced to date. Snn is a membrane-bound protein and is localized, in part, to the mitochondria and other vesicular organelles, suggesting that both localization and conservation are significant for the overall function of the protein. The structure of Snn in a micellar environment and its architecture in lipid bilayers have been determined using a combination of solution and solid-state NMR, respectively. Snn structure comprised a single transmembrane domain (residues 10-33), a 28-residue linker region from residues 34-60 that contains a conserved CXC metal binding motif and a putative 14-3-3ξ binding region, and a cytoplasmic helix (residues 61-79), which is partially embedded into the membrane. Of primary interest is understanding how this highly-conserved peptide with an interesting structure and cellular localization transmits both normal and potentially toxic signals within the cell. Evidence to date suggests that organotins such as trimethyltin interact with the CXC region of Snn, which is vicinal to the putative 14-3-3 binding site. In vitro transfection analyses and microarray experiments have inferred a possible role of Snn in several key signaling systems, including activation of the p38-ERK cascade, p53-dependent pathways, and 14-3-3ξ protein-mediated processes. TNFa can induce Snn mRNA expression in endothelial cells in a PKC-ε dependent manner. Studies with Snn siRNA suggest that this protein may be involved in growth regulation, since inhibition of Snn expression alone leads to reduced endothelial cells growth and induction of COP-1, a negative regulator of p53 function. A key piece of the puzzle, however, is how and why such a highly-conserved protein, localized to mitochondria, interacts with other regulatory proteins to alter growth and apoptosis. By knowing the structure, location, and possible signaling pathways involved, we propose that Snn constitutes an important sensor of mitochondrial damage, and plays a key role in the mediation of crosstalk between mitochondrial and nuclear compartments in specific cell types.

Original languageEnglish (US)
Pages (from-to)243-250
Number of pages8
JournalJournal of cellular biochemistry
Volume98
Issue number2
DOIs
StatePublished - May 15 2006

Fingerprint

Toxicity
Structural properties
Wounds and Injuries
Growth
Proteins
Mitochondria
Endothelial cells
stannin
Vertebrates
Conservation
Coat Protein Complex I
Endothelial Cells
Genes
Apoptosis
14-3-3 Proteins
Membranes
Lipid bilayers
Poisons
Lipid Bilayers
Cell growth

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Billingsley, M. L. ; Yun, J. ; Reese, B. E. ; Davidson, C. E. ; Buck-Koehntop, B. A. ; Veglia, G. / Functional and structural properties of stannin : Roles in cellular growth, selective toxicity, and mitochondrial responses to injury. In: Journal of cellular biochemistry. 2006 ; Vol. 98, No. 2. pp. 243-250.
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Functional and structural properties of stannin : Roles in cellular growth, selective toxicity, and mitochondrial responses to injury. / Billingsley, M. L.; Yun, J.; Reese, B. E.; Davidson, C. E.; Buck-Koehntop, B. A.; Veglia, G.

In: Journal of cellular biochemistry, Vol. 98, No. 2, 15.05.2006, p. 243-250.

Research output: Contribution to journalReview article

TY - JOUR

T1 - Functional and structural properties of stannin

T2 - Roles in cellular growth, selective toxicity, and mitochondrial responses to injury

AU - Billingsley, M. L.

AU - Yun, J.

AU - Reese, B. E.

AU - Davidson, C. E.

AU - Buck-Koehntop, B. A.

AU - Veglia, G.

PY - 2006/5/15

Y1 - 2006/5/15

N2 - Stannin (Snn) was discovered using subtractive hybridization methodology designed to find gene products related to selective organotin toxicity and apoptosis. The cDNAs for Snn were first isolated from brain tissues sensitive to trimethyltin, and were subsequently used to localize, characterize, and identify genomic DNA, and other gene products of Snn. Snn is a highly conserved, 88 amino acid protein found primarily in vertebrates. There is a minor divergence in the C-terminal sequence between amphibians and primates, but a nearly complete conservation of the first 60 residues in all vertebrates sequenced to date. Snn is a membrane-bound protein and is localized, in part, to the mitochondria and other vesicular organelles, suggesting that both localization and conservation are significant for the overall function of the protein. The structure of Snn in a micellar environment and its architecture in lipid bilayers have been determined using a combination of solution and solid-state NMR, respectively. Snn structure comprised a single transmembrane domain (residues 10-33), a 28-residue linker region from residues 34-60 that contains a conserved CXC metal binding motif and a putative 14-3-3ξ binding region, and a cytoplasmic helix (residues 61-79), which is partially embedded into the membrane. Of primary interest is understanding how this highly-conserved peptide with an interesting structure and cellular localization transmits both normal and potentially toxic signals within the cell. Evidence to date suggests that organotins such as trimethyltin interact with the CXC region of Snn, which is vicinal to the putative 14-3-3 binding site. In vitro transfection analyses and microarray experiments have inferred a possible role of Snn in several key signaling systems, including activation of the p38-ERK cascade, p53-dependent pathways, and 14-3-3ξ protein-mediated processes. TNFa can induce Snn mRNA expression in endothelial cells in a PKC-ε dependent manner. Studies with Snn siRNA suggest that this protein may be involved in growth regulation, since inhibition of Snn expression alone leads to reduced endothelial cells growth and induction of COP-1, a negative regulator of p53 function. A key piece of the puzzle, however, is how and why such a highly-conserved protein, localized to mitochondria, interacts with other regulatory proteins to alter growth and apoptosis. By knowing the structure, location, and possible signaling pathways involved, we propose that Snn constitutes an important sensor of mitochondrial damage, and plays a key role in the mediation of crosstalk between mitochondrial and nuclear compartments in specific cell types.

AB - Stannin (Snn) was discovered using subtractive hybridization methodology designed to find gene products related to selective organotin toxicity and apoptosis. The cDNAs for Snn were first isolated from brain tissues sensitive to trimethyltin, and were subsequently used to localize, characterize, and identify genomic DNA, and other gene products of Snn. Snn is a highly conserved, 88 amino acid protein found primarily in vertebrates. There is a minor divergence in the C-terminal sequence between amphibians and primates, but a nearly complete conservation of the first 60 residues in all vertebrates sequenced to date. Snn is a membrane-bound protein and is localized, in part, to the mitochondria and other vesicular organelles, suggesting that both localization and conservation are significant for the overall function of the protein. The structure of Snn in a micellar environment and its architecture in lipid bilayers have been determined using a combination of solution and solid-state NMR, respectively. Snn structure comprised a single transmembrane domain (residues 10-33), a 28-residue linker region from residues 34-60 that contains a conserved CXC metal binding motif and a putative 14-3-3ξ binding region, and a cytoplasmic helix (residues 61-79), which is partially embedded into the membrane. Of primary interest is understanding how this highly-conserved peptide with an interesting structure and cellular localization transmits both normal and potentially toxic signals within the cell. Evidence to date suggests that organotins such as trimethyltin interact with the CXC region of Snn, which is vicinal to the putative 14-3-3 binding site. In vitro transfection analyses and microarray experiments have inferred a possible role of Snn in several key signaling systems, including activation of the p38-ERK cascade, p53-dependent pathways, and 14-3-3ξ protein-mediated processes. TNFa can induce Snn mRNA expression in endothelial cells in a PKC-ε dependent manner. Studies with Snn siRNA suggest that this protein may be involved in growth regulation, since inhibition of Snn expression alone leads to reduced endothelial cells growth and induction of COP-1, a negative regulator of p53 function. A key piece of the puzzle, however, is how and why such a highly-conserved protein, localized to mitochondria, interacts with other regulatory proteins to alter growth and apoptosis. By knowing the structure, location, and possible signaling pathways involved, we propose that Snn constitutes an important sensor of mitochondrial damage, and plays a key role in the mediation of crosstalk between mitochondrial and nuclear compartments in specific cell types.

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