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Mol Pharmacol
2007 Oct 01;724:838-49. doi: 10.1124/mol.107.035527.
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Structural determinates for apolipoprotein E-derived peptide interaction with the alpha7 nicotinic acetylcholine receptor.
Gay EA
,
Bienstock RJ
,
Lamb PW
,
Yakel JL
.
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Neuronal nicotinic acetylcholine receptor (nAChR) signaling has been implicated in a variety of normal central nervous system (CNS) functions as well as an array of neuropathologies. Previous studies have demonstrated both neurotoxic and neuroprotective actions of peptides derived from apolipoprotein E (apoE). It has been discovered that apoE-derived peptides inhibit native and recombinant alpha7-containing nAChRs, indicating a direct interaction between apoE peptides and nAChRs. To probe the structure/function interaction between alpha7 nAChRs and the apoE peptide apoE(141-148), experiments were conducted in Xenopus laevis oocytes expressing wild-type and mutated nAChRs. Mutation of Trp55 to alanine blocks apoE peptide-induced inhibition of acetylcholine (ACh)-mediated alpha7 nAChR responses. Additional mutations at Trp55 suggest that hydrophobic interactions between the receptor and apoE(141-148) are essential for inhibition of alpha7 nAChR function. A mutated apoE peptide also demonstrated decreased inhibition at alpha7-W55A nAChRs as well as activity-dependent inhibition of both wild-type alpha7 nAChRs and alpha7-W55A receptors. Finally, a three-dimensional model of the alpha7 nAChR was developed based on the recently refined Torpedo marmorata nACh receptor. A structural model is proposed for the binding of apoE(141-148) to the alpha7 nAChR where the peptide binds at the interface between two subunits, near the ACh binding site. Similar to the functional data, the computational docking suggests the importance of hydrophobic interactions between the alpha7 nAChR and the apoE peptide for inhibition of receptor function. The current data suggest a mode for apoE peptide binding that directly blocks alpha7 nAChR activity and consequently may disrupt nAChR signaling.
Berg,
Nicotinic alpha 7 receptors: synaptic options and downstream signaling in neurons.
2002, Pubmed
Berg,
Nicotinic alpha 7 receptors: synaptic options and downstream signaling in neurons.
2002,
Pubmed
Brejc,
Crystal structure of an ACh-binding protein reveals the ligand-binding domain of nicotinic receptors.
2001,
Pubmed
Celie,
Nicotine and carbamylcholine binding to nicotinic acetylcholine receptors as studied in AChBP crystal structures.
2004,
Pubmed
Celie,
Crystal structure of nicotinic acetylcholine receptor homolog AChBP in complex with an alpha-conotoxin PnIA variant.
2005,
Pubmed
,
Xenbase
Celie,
Crystal structure of acetylcholine-binding protein from Bulinus truncatus reveals the conserved structural scaffold and sites of variation in nicotinic acetylcholine receptors.
2005,
Pubmed
Chen,
ZDOCK: an initial-stage protein-docking algorithm.
2003,
Pubmed
Clay,
Localization of a domain in apolipoprotein E with both cytostatic and cytotoxic activity.
1995,
Pubmed
Colquhoun,
Binding, gating, affinity and efficacy: the interpretation of structure-activity relationships for agonists and of the effects of mutating receptors.
1998,
Pubmed
Corringer,
Identification of a new component of the agonist binding site of the nicotinic alpha 7 homooligomeric receptor.
1995,
Pubmed
Corringer,
Nicotinic receptors at the amino acid level.
2000,
Pubmed
Dutertre,
Toxin insights into nicotinic acetylcholine receptors.
2006,
Pubmed
Ellison,
Alpha-conotoxins ImI and ImII. Similar alpha 7 nicotinic receptor antagonists act at different sites.
2003,
Pubmed
Fruchart-Gaillard,
Experimentally based model of a complex between a snake toxin and the alpha 7 nicotinic receptor.
2002,
Pubmed
Gay,
Apolipoprotein E-derived peptides block alpha7 neuronal nicotinic acetylcholine receptors expressed in xenopus oocytes.
2006,
Pubmed
,
Xenbase
Hansen,
Structures of Aplysia AChBP complexes with nicotinic agonists and antagonists reveal distinctive binding interfaces and conformations.
2005,
Pubmed
Hansen,
Galanthamine and non-competitive inhibitor binding to ACh-binding protein: evidence for a binding site on non-alpha-subunit interfaces of heteromeric neuronal nicotinic receptors.
2007,
Pubmed
Hansen,
Structural characterization of agonist and antagonist-bound acetylcholine-binding protein from Aplysia californica.
2006,
Pubmed
Holm,
Dali: a network tool for protein structure comparison.
1995,
Pubmed
Holm,
DaliLite workbench for protein structure comparison.
2000,
Pubmed
Jones,
Nicotinic receptors in the brain: correlating physiology with function.
1999,
Pubmed
Klein,
Inhibition of nicotinic acetylcholine receptors by apolipoprotein E-derived peptides in rat hippocampal slices.
2004,
Pubmed
Laskowitz,
Apolipoprotein E-derived peptides reduce CNS inflammation: implications for therapy of neurological disease.
2006,
Pubmed
Le Novère,
Models of the extracellular domain of the nicotinic receptors and of agonist- and Ca2+-binding sites.
2002,
Pubmed
Levin,
Nicotinic receptor subtypes and cognitive function.
2002,
Pubmed
Li,
RDOCK: refinement of rigid-body protein docking predictions.
2003,
Pubmed
Li,
Apolipoprotein E-derived peptides ameliorate clinical disability and inflammatory infiltrates into the spinal cord in a murine model of multiple sclerosis.
2006,
Pubmed
Lynch,
A novel therapeutic derived from apolipoprotein E reduces brain inflammation and improves outcome after closed head injury.
2005,
Pubmed
Marques,
A thrombin cleavage fragment of apolipoprotein E exhibits isoform-specific neurotoxicity.
1996,
Pubmed
McAdoo,
Intrathecal administration of a novel apoE-derived therapeutic peptide improves outcome following perinatal hypoxic-ischemic injury.
2005,
Pubmed
Morris,
Stereochemical quality of protein structure coordinates.
1992,
Pubmed
Nozaki,
The solubility of amino acids and two glycine peptides in aqueous ethanol and dioxane solutions. Establishment of a hydrophobicity scale.
1971,
Pubmed
Pavlov,
Controlling inflammation: the cholinergic anti-inflammatory pathway.
2006,
Pubmed
Picciotto,
Nicotinic receptors in aging and dementia.
2002,
Pubmed
Raggenbass,
Nicotinic receptors in circuit excitability and epilepsy.
2002,
Pubmed
Segelke,
Conformational flexibility in the apolipoprotein E amino-terminal domain structure determined from three new crystal forms: implications for lipid binding.
2000,
Pubmed
Sine,
The nicotinic receptor ligand binding domain.
2002,
Pubmed
Spier,
The role of tryptophan residues in the 5-Hydroxytryptamine(3) receptor ligand binding domain.
2000,
Pubmed
Tolar,
Neurotoxicity of the 22 kDa thrombin-cleavage fragment of apolipoprotein E and related synthetic peptides is receptor-mediated.
1997,
Pubmed
Ulens,
Structural determinants of selective alpha-conotoxin binding to a nicotinic acetylcholine receptor homolog AChBP.
2006,
Pubmed
Unwin,
Refined structure of the nicotinic acetylcholine receptor at 4A resolution.
2005,
Pubmed
Wiehe,
ZDOCK and RDOCK performance in CAPRI rounds 3, 4, and 5.
2005,
Pubmed
Xie,
Contributions of Torpedo nicotinic acetylcholine receptor gamma Trp-55 and delta Trp-57 to agonist and competitive antagonist function.
2001,
Pubmed
,
Xenbase
Young,
Species selectivity of a nicotinic acetylcholine receptor agonist is conferred by two adjacent extracellular beta4 amino acids that are implicated in the coupling of binding to channel gating.
2007,
Pubmed
Zamyatnin,
Protein volume in solution.
1972,
Pubmed
