A Calpha model for the transmembrane alpha helices of gap junction intercellular channels.
Gap junction channels connect the cytoplasms of apposed cells via an intercellular conduit formed by the end-to-end docking of two hexameric hemichannels called connexons. We used electron cryomicroscopy to derive a three-dimensional density map at 5.7 angstroms in-plane and 19.8 angstroms vertical resolution, allowing us to identify the positions and tilt angles for the 24 alpha helices within each hemichannel. The four hydrophobic segments in connexin sequences were assigned to the alpha helices in the map based on biochemical and phylogenetic data. Analyses of evolutionary conservation and compensatory mutations in connexin evolution identified the packing interfaces between the helices. The final model, which specifies the coordinates of Calpha atoms in the transmembrane domain, provides a structural basis for understanding the different physiological effects of almost 30 mutations and polymorphisms in terms of structural deformations at the interfaces between helices, revealing an intimate connection between molecular structure and disease.
Fleishman
Sarel J
SJ
Department of Biochemistry, George S. Wise Faculty of Life Sciences, Tel-Aviv University, Ramat Aviv, 69978, Israel.
Unger
Vinzenz M
VM
Yeager
Mark
M
Ben-Tal
Nir
N
D000595:Amino Acid Sequence; D017630:Connexins / Q000737:chemistry / Q000235:genetics / Q000648:ultrastructure; D017124:Conserved Sequence; D020285:Cryoelectron Microscopy; D017629:Gap Junctions / Q000737:chemistry* / Q000648:ultrastructure; D006801:Humans; D007473:Ion Channels / Q000737:chemistry*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D010802:Phylogeny; D011110:Polymorphism, Genetic; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D017386:Sequence Homology, Amino Acid; D013329:Structure-Activity Relationship; D000097002:Gap Junction beta-1 Protein
D017630:Connexins; D007473:Ion Channels; D000097002:Gap Junction beta-1 Protein