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Title: Structural principles of distinct assemblies of the human α4β2 nicotinic receptor

Abstract

Fast chemical communication in the nervous system is mediated by neurotransmitter-gated ion channels. The prototypical member of this class of cell surface receptors is the cation-selective nicotinic acetylcholine receptor. As with most ligand-gated ion channels, nicotinic receptors assemble as oligomers of subunits, usually as hetero-oligomers and often with variable stoichiometries. This intrinsic heterogeneity in protein composition provides fine tunability in channel properties, which is essential to brain function, but frustrates structural and biophysical characterization. The α4β2 subtype of the nicotinic acetylcholine receptor is the most abundant isoform in the human brain and is the principal target in nicotine addiction. This pentameric ligand-gated ion channel assembles in two stoichiometries of α- and β-subunits (2α:3β and 3α:2β). Both assemblies are functional and have distinct biophysical properties, and an imbalance in the ratio of assemblies is linked to both nicotine addiction and congenital epilepsy. Here we leverage cryo-electron microscopy to obtain structures of both receptor assemblies from a single sample. Antibody fragments specific to β2 were used to ‘break’ symmetry during particle alignment and to obtain high-resolution reconstructions of receptors of both stoichiometries in complex with nicotine. Furthermore, the results reveal principles of subunit assembly and the structural basis of the distinctive biophysicalmore » and pharmacological properties of the two different stoichiometries of this receptor.« less

Authors:
 [1];  [2];  [1];  [1];  [1];  [1]
  1. Univ. of Texas Southwestern Medical Center, Dallas, TX (United States)
  2. Stanford Univ., Stanford, CA (United States); SLAC National Accelerator Lab., Menlo Park, CA (United States)
Publication Date:
Research Org.:
SLAC National Accelerator Lab., Menlo Park, CA (United States)
Sponsoring Org.:
USDOE
OSTI Identifier:
1461187
Grant/Contract Number:  
AC02-76SF00515
Resource Type:
Accepted Manuscript
Journal Name:
Nature (London)
Additional Journal Information:
Journal Name: Nature (London); Journal Volume: 557; Journal Issue: 7704; Journal ID: ISSN 0028-0836
Publisher:
Nature Publishing Group
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES

Citation Formats

Walsh, Jr., Richard M., Roh, Soung -Hun, Gharpure, Anant, Morales-Perez, Claudio L., Teng, Jinfeng, and Hibbs, Ryan E. Structural principles of distinct assemblies of the human α4β2 nicotinic receptor. United States: N. p., 2018. Web. doi:10.1038/s41586-018-0081-7.
Walsh, Jr., Richard M., Roh, Soung -Hun, Gharpure, Anant, Morales-Perez, Claudio L., Teng, Jinfeng, & Hibbs, Ryan E. Structural principles of distinct assemblies of the human α4β2 nicotinic receptor. United States. doi:10.1038/s41586-018-0081-7.
Walsh, Jr., Richard M., Roh, Soung -Hun, Gharpure, Anant, Morales-Perez, Claudio L., Teng, Jinfeng, and Hibbs, Ryan E. Wed . "Structural principles of distinct assemblies of the human α4β2 nicotinic receptor". United States. doi:10.1038/s41586-018-0081-7. https://www.osti.gov/servlets/purl/1461187.
@article{osti_1461187,
title = {Structural principles of distinct assemblies of the human α4β2 nicotinic receptor},
author = {Walsh, Jr., Richard M. and Roh, Soung -Hun and Gharpure, Anant and Morales-Perez, Claudio L. and Teng, Jinfeng and Hibbs, Ryan E.},
abstractNote = {Fast chemical communication in the nervous system is mediated by neurotransmitter-gated ion channels. The prototypical member of this class of cell surface receptors is the cation-selective nicotinic acetylcholine receptor. As with most ligand-gated ion channels, nicotinic receptors assemble as oligomers of subunits, usually as hetero-oligomers and often with variable stoichiometries. This intrinsic heterogeneity in protein composition provides fine tunability in channel properties, which is essential to brain function, but frustrates structural and biophysical characterization. The α4β2 subtype of the nicotinic acetylcholine receptor is the most abundant isoform in the human brain and is the principal target in nicotine addiction. This pentameric ligand-gated ion channel assembles in two stoichiometries of α- and β-subunits (2α:3β and 3α:2β). Both assemblies are functional and have distinct biophysical properties, and an imbalance in the ratio of assemblies is linked to both nicotine addiction and congenital epilepsy. Here we leverage cryo-electron microscopy to obtain structures of both receptor assemblies from a single sample. Antibody fragments specific to β2 were used to ‘break’ symmetry during particle alignment and to obtain high-resolution reconstructions of receptors of both stoichiometries in complex with nicotine. Furthermore, the results reveal principles of subunit assembly and the structural basis of the distinctive biophysical and pharmacological properties of the two different stoichiometries of this receptor.},
doi = {10.1038/s41586-018-0081-7},
journal = {Nature (London)},
number = 7704,
volume = 557,
place = {United States},
year = {2018},
month = {5}
}

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