Abstract
Gap junction channels facilitate the intercellular exchange of ions and small molecules, a process that is critical for the function of many different kinds of cells and tissues. Recent crystal structures of channels formed by one connexin isoform (connexin26) have been determined, and they have been subjected to molecular modeling. These studies have provided high-resolution models to gain insights into the mechanisms of channel conductance, molecular permeability, and gating. The models share similarities, but there are some differences in the conclusions reached by these studies. Many unanswered questions remain to allow an atomic-level understanding of intercellular communication mediated by connexin26. Because some domains of the connexin polypeptides are highly conserved (like the transmembrane regions), it is likely that some features of the connexin26 structure will apply to other members of the family of gap junction proteins. However, determination of high-resolution structures and modeling of other connexin channels will be required to account for the diverse biophysical properties and regulation conferred by the differences in their sequences.
Highlights
Intercellular communication through gap junction channels is critical for integrating the functions of cells in the tissues of all multicellular organisms by allowing direct exchange of ions and small molecules
The importance of gap junctions is supported by the wide range of abnormalities linked to connexin mutations or caused by disrupting connexin expression
This study suggested that the Cx32 gap junction channel has a similar architecture of transmembrane domains (TMs) to both the Cx26 structure and its equilibrated molecular dynamics model, including the presence of IC pockets[48]
Summary
Intercellular communication through gap junction channels is critical for integrating the functions of cells in the tissues of all multicellular organisms by allowing direct exchange of ions and small molecules. Knowledge of the amino acid residues important for docking has helped elucidate the molecular mechanism of malfunction of some disease-associated connexins In their studies of a cataractlinked mutant (Cx46N188T), which forms functional hemichannels (but not intercellular channels), Schadzek et al constructed models of Cx46 based on the Cx26 structure that allowed them to conclude that the mutated amino acid is critical for the docking of hemichannels through the formation of hydrogen bonds with the opposing hemichannel[50]. To gain insights into gating by divalent cations, Bennett et al determined the X-ray structures of the human Cx26 gap junction channel crystallized in the presence or absence of calcium ions[22] These two structures showed rather small conformational differences but identified calcium coordination sites (the carboxylate of E47 and carbonyl oxygen of G45 from one monomer and the carboxylate of E42 in the adjacent monomer). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript
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