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Open Access

Permeation Pathway of Homomeric Connexin 26 and Connexin 30 Channels Investigated by Molecular Dynamics

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.

This article can be cited as:
F. Zonta, G. Polles, G. Zanotti, F. Mammano, Permeation Pathway of Homomeric Connexin 26 and Connexin 30 Channels Investigated by Molecular DynamicsJ. Biomol Struct Dyn 29(5), 985-998 (2012).

Francesco Zonta1,2
Guido Polles3
Giuseppe Zanotti3,4
Fabio Mammano1,2,3,5*

1Department of Physics and Astronomy “G.Galilei”, University of Padua, 35129 Padua, Italy
2Consorzio Nazionale Universitario per le Scienze Fisiche della Materia (CNISM), 35129 Padua, Italy
3Venetian Institute of Molecular Medicine, Foundation for Advanced Biomedical Research, 35129 Padua, Italy
4Department of Biological Chemistry, University of Padua, 35129 Padua, Italy
5CNR Institute of Neurosciences, Padua Section, 35121 Padua, Italy

*Corresponding author:
Fabio Mammano
Phone/Fax: 139 049 7923 231/266
E-mail: fabio.mammano@unipd.it

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