Structural principles of distinct assemblies of the human α4β2 nicotinic receptor

Walsh, Jr., Richard M.; Roh, Soung -Hun; Gharpure, Anant; Morales-Perez, Claudio L.; Teng, Jinfeng; Hibbs, Ryan E.

doi:10.1038/s41586-018-0081-7

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

Journal Article · Wed May 02 00:00:00 EDT 2018 · Nature (London)

DOI:https://doi.org/10.1038/s41586-018-0081-7· OSTI ID:1461187

Walsh, Jr., Richard M. ^[1]; Roh, Soung -Hun ^[2]; Gharpure, Anant ^[1]; Morales-Perez, Claudio L. ^[1]; Teng, Jinfeng ^[1]; Hibbs, Ryan E. ^[1]

Univ. of Texas Southwestern Medical Center, Dallas, TX (United States)
Stanford Univ., Stanford, CA (United States); SLAC National Accelerator Lab., Menlo Park, CA (United States)

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.

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Research Organization:: SLAC National Accelerator Laboratory (SLAC), Menlo Park, CA (United States)

Sponsoring Organization:: USDOE

Grant/Contract Number:: AC02-76SF00515

OSTI ID:: 1461187

Journal Information:: Nature (London), Vol. 557, Issue 7704; ISSN 0028-0836

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: English

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Cited by: 119 works

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