title: Permeation pathway of homomeric connexin 26 and connexin 30 channels investigated by molecular dynamics.
abstract: Mutations in the genes GJB2 and GJB6 encoding human connnexin26 (hCx26) and connexin30 (hCx30), respectively, are the leading cause of non-syndromic prelingual deafness in several human populations. In this work, we exploited the high degree (77%) of sequence similarity shared by hCx26 and hCx30 to create atomistic models of homomeric hCx26 and hCx30 connexons starting from the X-ray crystallographic structure of an intercellular channel formed by hCx26 protomers at 3.5-å resolution. The equilibrium dynamics of the two protein complexes was followed for 40 ns each by Molecular Dynamics (MD) simulations. Our results indicate that, in hCx26, positively charged Lys41 residues establish a potential barrier within the fully open channel, hindering ion diffusion in the absence of an electrochemical gradient. A similar role is played, in hCx30, by negatively charged Glu49 residues. The different position and charge of these two ion sieves account for the differences in unitary conductance observed experimentally. Our results are discussed in terms of present models of voltage gating in connexin channels.
authors.affiliation: Department of Physics and Astronomy G.Galilei, University of Padua, 35129 Padua, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Zonta
authors.forename: Guido
authors.initials: G
authors.lastname: Polles
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Zanotti
authors.forename: Fabio
authors.initials: F
authors.lastname: Mammano
mesh_terms: D000595:Amino Acid Sequence; D002118:Calcium / Q000378:metabolism; D002462:Cell Membrane / Q000737:chemistry; D000072259:Connexin 26; D000075302:Connexin 30; D017630:Connexins / Q000737:chemistry* / Q000378:metabolism; D018360:Crystallography, X-Ray; D003638:Deafness / Q000235:genetics; D006801:Humans; D008239:Lysine / Q000737:chemistry; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D010743:Phospholipids / Q000737:chemistry; D011487:Protein Conformation
chemical_list: D000075302:Connexin 30; D017630:Connexins; C000607042:GJB2 protein, human; C491020:GJB6 protein, human; D010743:Phospholipids; D000072259:Connexin 26; D008239:Lysine; D002118:Calcium