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Sequence and Phylogenetic Analyses of 4 TMS Junctional Proteins of Animals: Connexins, Innexins, Claudins and Occludins

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Abstract

Connexins and probably innexins are the principal constituents of gap junctions, while claudins and occludins are principal tight junctional constituents. All have similar topologies with four α-helical transmembrane segments (TMSs), and all exhibit well-conserved extracytoplasmic cysteines that either are known to or potentially can form disulfide bridges. We have conducted sequence, topological and phylogenetic analyses of the proteins that comprise the connexin, innexin, claudin and occludin families. A multiple alignment of the sequences of each family was used to derive average hydropathy and similarity plots as well as phylogenetic trees. Analyses of the data generated led to the following evolutionary and functional suggestions: (1) In all four families, the most conserved regions of the proteins from each family are the four TMSs although the extracytoplasmic loops between TMSs 1 and 2, and TMSs 3 and 4 are usually well conserved. (2) The phylogenetic trees revealed sets of orthologues except for the innexins where phylogeny primarily reflects organismal source, probably due to a lack of relevant organismal sequence data. (3) The two halves of the connexins exhibit similarities suggesting that they were derived from a common origin by an internal gene duplication event. (4) Conserved cysteyl residues in the connexins and innexins may point to a similar extracellular structure involved in the docking of hemichannels to create intercellular communication channels. (5) We suggest a similar role in homomeric interactions for conserved extracellular residues in the claudins and occludins. The lack of sequence or motif similarity between the four different families indicates that, if they did evolve from a common ancestral gene, they have diverged considerably to fulfill separate, novel functions. We suggest that internal duplication was a general evolutionary strategy used to generate new families of channels and junctions with unique functions. These findings and suggestions should serve as guides for future studies concerning the structures, functions and evolutionary origins of junctional proteins.

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Notes

  1. Figures on the website: (http://www-biology.ucsd.edu/~msaier/transport/ ); Fig. S1 Multiple alignment of all connexins; Fig. S2 Multiple alignment of the 22 human connexins; Fig. S3 Phylogenetic tree of the 22 human connexins; Fig. S4 Multiple alignment of all innexins; Fig. S5 Multiple alignment of all claudins; Fig. S6 Multiple alignment of all occludins.

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Acknowledgements

We thank Mary Beth Miller for assistance in the preparation of this manuscript. This work was supported by NIH grants GM55434 and GM64368 from the National Institute of General Medical Sciences (to MHS), an NEI grant EY13605 (to NMK), an RPB grant of unrestricted funds from Research to Prevent Blindness (to the UIC), and a grant from the Danish Research Council (to PAN).

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  1. Division of Biology, University of California at San Diego, 9500 Gilman Dr., La Jolla, CA 92093-0116, USA

    V. B. Hua, A. B. Chang, J. H. Tchieu & M. H. Saier Jr

  2. Department of Cell Biology, The Scripps Research Institute, La Jolla, CA 92037, USA

    N. M. Kumar & P. A. Nielsen

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  1. V. B. Hua
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Hua, V., Chang, A., Tchieu, J. et al. Sequence and Phylogenetic Analyses of 4 TMS Junctional Proteins of Animals: Connexins, Innexins, Claudins and Occludins . J. Membrane Biol. 194, 59–76 (2003). https://doi.org/10.1007/s00232-003-2026-8

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