Structure of cardiac gap junction intercellular channels.
Gap junction proteins, termed connexins, constitute a multigene family of polytopic membrane channel proteins that have four hydrophobic transmembrane domains with the N- and C-termini located on the cytoplasmic membrane face. The principal gap junction protein in the heart, alpha 1 connexin (also designated Cx43), mediates action potential propagation between cells in order to synchronize cardiac contraction. alpha 1 connexin channels are concentrated in gap junction plaques located in the intercalated disks. The intercellular channel is formed by the docking of two hemi-channels, termed connexons, formed by a ring of six 43-kDa alpha 1 connexin subunits. Each subunit is asymmetric with an axial ratio of 4-5:1 with approximately 20 A extending into the extracellular gap approximately 50 A spanning the lipid bilayer and approximately 50 A extending into the cytoplasmic space. We have recently grown two-dimensional crystals of a recombinant C-terminal truncation mutant of alpha 1 connexin (designated alpha 1Cx263T) that are ordered to better than 7 A resolution. Projection density maps derived by electron cryocrystallography revealed that the intercellular channel is lined by six alpha-helices, and there is a second ring of six alpha-helices at the interface with the membrane lipids. These rings of alpha-helices are staggered by 30 degrees, which predicts that the two connexons in the channel are staggered by 30 degrees such that each connexin subunit in one connexon interacts with two subunits in the apposed connexon. Such a quaternary arrangement may confer stability in the docking of the connexons to form a tight electrical seal for intercellular current flow during cardiac conduction.
Yeager
M
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Department of Cell Biology, Scripps Research Institute, La Jolla, California 92037, USA.
D000595:Amino Acid Sequence; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D002942:Circular Dichroism; D018031:Connexin 43 / Q000737:chemistry* / Q000276:immunology / Q000648:ultrastructure; D018360:Crystallography, X-Ray; D017629:Gap Junctions / Q000737:chemistry* / Q000648:ultrastructure; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007091:Image Processing, Computer-Assisted; D015640:Ion Channel Gating; D007473:Ion Channels / Q000737:chemistry* / Q000276:immunology / Q000648:ultrastructure; D008564:Membrane Potentials; D008854:Microscopy, Electron; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009124:Muscle Proteins / Q000737:chemistry* / Q000276:immunology / Q000648:ultrastructure; D009206:Myocardium / Q000737:chemistry*; D010446:Peptide Fragments / Q000276:immunology; D011487:Protein Conformation; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000737:chemistry; D012399:Rotation; D015398:Signal Transduction; D013329:Structure-Activity Relationship
D000911:Antibodies, Monoclonal; D018031:Connexin 43; D007473:Ion Channels; D009124:Muscle Proteins; D010446:Peptide Fragments; D011993:Recombinant Fusion Proteins