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Structure-function correlation analysis of connexin50 missense mutations causing congenital cataract: electrostatic potential alteration could determine intracellular trafficking fate of mutants.

Sarkar D, Ray K, Sengupta M - Biomed Res Int (2014)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Genetics, University of Calcutta, University College of Science, 35 Ballygunge Circular Road, Kolkata 700 019, India.

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.

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Correlation of alterations in the surface electrostatic potential in different Cx50 mutants with their intracellular trafficking fates. Four out of 6 mutations showing impaired trafficking (R23T, D47N, E201K, and R205G[Gja8]) involve S.E.P. change, while the other 2 mutations (P88S and P88Q) involve gross structural alteration. On the contrary, only 1 out of 4 mutations showing proper trafficking (V44E) involves S.E.P. change.
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fig4: Correlation of alterations in the surface electrostatic potential in different Cx50 mutants with their intracellular trafficking fates. Four out of 6 mutations showing impaired trafficking (R23T, D47N, E201K, and R205G[Gja8]) involve S.E.P. change, while the other 2 mutations (P88S and P88Q) involve gross structural alteration. On the contrary, only 1 out of 4 mutations showing proper trafficking (V44E) involves S.E.P. change.

Mentions: As mentioned above, R23T, R198Q/W, and E201K involve H-bond alteration; only the mutations R198Q/W involve induction of steric clash while several mutations involved changes in surface electrostatic potential. We tried to correlate the alterations in the surface electrostatic potential in different mutants with their intracellular trafficking fates (Figure 4). It is evident that, while 4/6 mutants showing impaired trafficking (R23T, D47N, E201K, and R205G[Gja8]) involve change in surface electrostatic potential, the other 2 mutants (P88S and P88Q) involve gross structural alteration (loss of kink in TM2). On the contrary, only 1/4 mutants showing proper trafficking (V44E) involves surface electrostatic potential alteration. This observation is suggestive of the fact that surface electrostatic potential alteration could be a potential determinant of the intracellular trafficking fate of Cx50 missense mutants.


Structure-function correlation analysis of connexin50 missense mutations causing congenital cataract: electrostatic potential alteration could determine intracellular trafficking fate of mutants.

Sarkar D, Ray K, Sengupta M - Biomed Res Int (2014)

Correlation of alterations in the surface electrostatic potential in different Cx50 mutants with their intracellular trafficking fates. Four out of 6 mutations showing impaired trafficking (R23T, D47N, E201K, and R205G[Gja8]) involve S.E.P. change, while the other 2 mutations (P88S and P88Q) involve gross structural alteration. On the contrary, only 1 out of 4 mutations showing proper trafficking (V44E) involves S.E.P. change.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4066682&req=5

fig4: Correlation of alterations in the surface electrostatic potential in different Cx50 mutants with their intracellular trafficking fates. Four out of 6 mutations showing impaired trafficking (R23T, D47N, E201K, and R205G[Gja8]) involve S.E.P. change, while the other 2 mutations (P88S and P88Q) involve gross structural alteration. On the contrary, only 1 out of 4 mutations showing proper trafficking (V44E) involves S.E.P. change.
Mentions: As mentioned above, R23T, R198Q/W, and E201K involve H-bond alteration; only the mutations R198Q/W involve induction of steric clash while several mutations involved changes in surface electrostatic potential. We tried to correlate the alterations in the surface electrostatic potential in different mutants with their intracellular trafficking fates (Figure 4). It is evident that, while 4/6 mutants showing impaired trafficking (R23T, D47N, E201K, and R205G[Gja8]) involve change in surface electrostatic potential, the other 2 mutants (P88S and P88Q) involve gross structural alteration (loss of kink in TM2). On the contrary, only 1/4 mutants showing proper trafficking (V44E) involves surface electrostatic potential alteration. This observation is suggestive of the fact that surface electrostatic potential alteration could be a potential determinant of the intracellular trafficking fate of Cx50 missense mutants.

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Genetics, University of Calcutta, University College of Science, 35 Ballygunge Circular Road, Kolkata 700 019, India.

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.

Show MeSH
Related in: MedlinePlus