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Structural Determinates for Apolipoprotein E-Derived Peptide Interaction with the 7 Nicotinic Acetylcholine Receptor

Laboratory of Neurobiology (E.A.G., P.W.L., J.L.Y.), Scientific Computing Laboratory (R.J.B.), National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, North Carolina

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 7-containing nAChRs, indicating a direct interaction between apoE peptides and nAChRs. To probe the structure/function interaction between 7 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 7 nAChR responses. Additional mutations at Trp55 suggest that hydrophobic interactions between the receptor and apoE_141–148 are essential for inhibition of 7 nAChR function. A mutated apoE peptide also demonstrated decreased inhibition at 7-W55A nAChRs as well as activity-dependent inhibition of both wild-type 7 nAChRs and 7-W55A receptors. Finally, a three-dimensional model of the 7 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 7 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 7 nAChR and the apoE peptide for inhibition of receptor function. The current data suggest a mode for apoE peptide binding that directly blocks 7 nAChR activity and consequently may disrupt nAChR signaling.

Received for publication February 26, 2007.

Accepted for publication July 3, 2007.

Address correspondence to: Jerrel L. Yakel, NIEHS, F2-08, P.O. Box 12233, 111 T. W. Alexander Drive, Research Triangle Park, NC 27709. E-mail: yakel{at}niehs.nih.gov

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