Document Detail


Permeation pathway of homomeric connexin 26 and connexin 30 channels investigated by molecular dynamics.
MedLine Citation:
PMID:  22292956     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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:
Francesco Zonta; Guido Polles; Giuseppe Zanotti; Fabio Mammano
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Journal of biomolecular structure & dynamics     Volume:  29     ISSN:  1538-0254     ISO Abbreviation:  J. Biomol. Struct. Dyn.     Publication Date:  2012  
Date Detail:
Created Date:  2012-02-01     Completed Date:  2012-10-31     Revised Date:  2013-06-26    
Medline Journal Info:
Nlm Unique ID:  8404176     Medline TA:  J Biomol Struct Dyn     Country:  United States    
Other Details:
Languages:  eng     Pagination:  985-98     Citation Subset:  IM    
Affiliation:
Department of Physics and Astronomy G.Galilei, University of Padua, 35129 Padua, Italy.
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MeSH Terms
Descriptor/Qualifier:
Amino Acid Sequence
Calcium / metabolism
Cell Membrane / chemistry
Connexins / chemistry*,  metabolism
Crystallography, X-Ray
Deafness / genetics
Humans
Lysine / chemistry
Models, Molecular
Molecular Dynamics Simulation
Molecular Sequence Data
Phospholipids / chemistry
Protein Conformation
Grant Support
ID/Acronym/Agency:
GGP09137//Telethon
Chemical
Reg. No./Substance:
0/Connexins; 0/GJB6 protein, human; 0/Phospholipids; 127120-53-0/connexin 26; 56-87-1/Lysine; 7440-70-2/Calcium
Comments/Corrections

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