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Molecular modeling and mutagenesis of gap junction channels

Academic Article
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Overview

authors

  • Kovacs, J. A.
  • Baker, K. A.
  • Altenberg, G. A.
  • Abagyan, R.
  • Yeager, Mark

publication date

  • May 2007

journal

  • Progress in Biophysics & Molecular Biology  Journal

abstract

  • Gap junction channels connect the cytoplasms of adjacent cells through the end-to-end docking of hexameric hemichannels called connexons. Each connexon is formed by a ring of 24 alpha-helices that are staggered by 30 degrees with respect to those in the apposed connexon. Current evidence suggests that the two connexons are docked by interdigitated, anti-parallel beta strands across the extracellular gap. The second extracellular loop, E2, guides selectivity in docking between connexons formed by different isoforms. There is considerably more sequence variability of the N-terminal portion of E2, suggesting that this region dictates connexon coupling. Mutagenesis, biochemical, dye-transfer and electrophysiological data, combined with computational studies, have suggested possible assignments for the four transmembrane alpha-helices within each subunit. Most current models assign M3 as the major pore-lining helix. Mapping of human mutations onto a C(alpha) model suggested that native helix packing is important for the formation of fully functional channels. Nevertheless, a mutant in which the M4 helix has been replaced with polyalanine is functional, suggesting that M4 is located on the perimeter of the channel. In spite of this substantial progress in understanding the structural biology of gap junction channels, an experimentally determined structure at atomic resolution will be essential to confirm these concepts.

subject areas

  • Amino Acid Sequence
  • Amino Acid Substitution
  • Computer Simulation
  • Connexins
  • Humans
  • Models, Chemical
  • Models, Molecular
  • Molecular Sequence Data
  • Protein Conformation
  • Structure-Activity Relationship
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Research

keywords

  • computational modeling
  • connexon
  • electron microscopy
  • gap junction channel
  • intercellular communication
  • mutagenesis
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Identity

PubMed Central ID

  • PMC2819402

International Standard Serial Number (ISSN)

  • 0079-6107

Digital Object Identifier (DOI)

  • 10.1016/j.pbiomolbio.2007.03.013

PubMed ID

  • 17524457
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Additional Document Info

start page

  • 15

end page

  • 28

volume

  • 94

issue

  • 1-2

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