Abstract
Connexin50 (Cx50) mutations are reported to cause congenital cataract probably through the disruption of intercellular transport in the lens. Cx50 mutants that undergo mistrafficking have generally been associated with failure to form functional gap junction channels; however, sometimes even properly trafficked mutants were found to undergo similar consequences. We hereby wanted to elucidate any structural bases of the varied functional consequences of Cx50 missense mutations through in silico approach. Computational studies have been done based on a Cx50 homology model to assess conservation, solvent accessibility, and 3-dimensional localization of mutated residues as well as mutation-induced changes in surface electrostatic potential, H-bonding, and steric clash. This was supplemented with meta-analysis of published literature on the functional properties of connexin missense mutations. Analyses revealed that the mutation-induced critical alterations of surface electrostatic potential in Cx50 mutants could determine their fate in intracellular trafficking. A similar pattern was observed in case of mutations involving corresponding conserved residues in other connexins also. Based on these results the trafficking fates of 10 uncharacterized Cx50 mutations have been predicted. Further experimental analyses are needed to validate the observed correlation.
Highlights
The intercellular transport of ions and metabolites via an extensive network of gap junctions is indispensible for the growth, development, and proper maintenance of the mammalian avascular lens
Previous functional studies of 12 Cx50 missense mutants revealed that those differed with respect to intracellular trafficking, hemichannel currents, gap junctional conductance/dye transfer activities, and dominant negative effects on WT Cx50
It is to be noted that R198W/R198Q human Cx50 mutants have not been functionally characterized, R205G involving the corresponding residue in mouse Gja8 has been characterized and in accordance we have included the R198 residue and the R198W/R198Q mutations in our analyses
Summary
The intercellular transport of ions and metabolites via an extensive network of gap junctions is indispensible for the growth, development, and proper maintenance of the mammalian avascular lens. Connexins (Cx) are the only gap junction proteins identified in the lens to date. The three isoforms of the connexins expressed in the lens are Cx43, Cx46, and Cx50 [1]. After being synthesized in the endoplasmic reticulum (ER) membrane, the connexin subunits oligomerize to form a hemichannel (or connexon) that is delivered to the plasma membrane. The end-to-end docking of two hemichannels forms a functional gap junction channel. Combination of different connexin isomers during channel formation can lead to homotypic, heterotypic, or heteromeric channels [1, 2]
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