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An ion selectivity filter in the extracellular domain of Cys-loop receptors reveals determinants for ion conductance

Academic Article
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Overview

authors

  • Hansen, Scott
  • Wang, H. L.
  • Taylor, P.
  • Sine, S. M.

publication date

  • December 2008

journal

  • Journal of Biological Chemistry  Journal

abstract

  • Neurotransmitter binding to Cys-loop receptors promotes a prodigious transmembrane flux of several million ions/s, but to date, structural determinants of ion flux have been identified flanking the membrane-spanning region. Using x-ray crystallography, sequence analysis, and single-channel recording, we identified a novel determinant of ion conductance near the point of entry of permeant ions. Co-crystallization of acetylcholine-binding protein with sulfate anions revealed coordination of SO4(2-) with a ring of lysines at a position equivalent to 24 A above the lipid membrane in homologous Cys-loop receptors. Analysis of multiple sequence alignments revealed that residues equivalent to the ring of lysines are negatively charged in cation-selective receptors but are positively charged in anion-selective receptors. Charge reversal of side chains at homologous positions in the nicotinic receptor from the motor end plate decreases unitary conductance up to 80%. Selectivity filters stemming from transmembrane alpha-helices have similar pore diameters and compositions of amino acids. These findings establish that when the channel opens under a physiological electrochemical gradient, permeant ions are initially stabilized within the extracellular vestibule of Cys-loop receptors, and this stabilization is a major determinant of ion conductance.

subject areas

  • Amino Acid Sequence
  • Animals
  • Cell Membrane
  • Crystallography, X-Ray
  • Cysteine
  • Cytoplasm
  • Humans
  • Ions
  • Models, Biological
  • Molecular Conformation
  • Molecular Sequence Data
  • Protein Structure, Secondary
  • Protein Structure, Tertiary
  • Receptors, Nicotinic
  • Sequence Homology, Amino Acid
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Identity

PubMed Central ID

  • PMC2662287

International Standard Serial Number (ISSN)

  • 0021-9258

Digital Object Identifier (DOI)

  • 10.1074/jbc.C800194200

PubMed ID

  • 18940802
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Additional Document Info

start page

  • 36066

end page

  • 36070

volume

  • 283

issue

  • 52

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