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Protein-protein interfaces from cytochrome c oxidase I evolve faster than nonbinding surfaces, yet negative selection is the driving force.

Aledo JC, Valverde H, Ruíz-Camacho M, Morilla I, López FD - Genome Biol Evol (2014)

Bottom Line: Herein, using evolutionary data in combination with structural information of COX, we show that failing to discern the effects of interaction from other structural and functional effects can lead to deceptive conclusions such as the "optimizing hypothesis." Once spurious factors have been accounted for, data analysis shows that mtDNA-encoded residues engaged in contacts are, in general, more constrained than their noncontact counterparts.This differential behavior cannot be explained on the basis of predicted thermodynamic stability, as interactions between mtDNA-encoded subunits contribute more weakly to the complex stability than those interactions between subunits encoded by different genomes.Therefore, the higher conservation observed among mtDNA-encoded residues involved in intragenome interactions is likely due to factors other than structural stability.

View Article: PubMed Central - PubMed

Affiliation: Departamento de Biología Molecular y Bioquímica, Facultad de Ciencias, Universidad de Málaga, Spain caledo@uma.es.

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Exposed Noncontact residues from COX I are much more conserved than expected from their destabilizing effect on the holoenzyme. The exposed residues from each mtDNA-encoded proteins were split into two groups: Contact (C) and noncontact (NC), according to the criteria given in the text. Afterwards, the ΣdN and mean ΔΔG were computed for each of these subsets. These two variables showed a significant negative correlation (n = 6, Pearson r = −0.774, P value = 0.035) that was improved when data corresponding to COX I Exposed Noncontact were excluded from the analysis (n = 5, Pearson r = −0.890, P value = 0.021). The inset shows the proportion of residues that have been described as functionally relevant among the Exposed Noncontact, in comparison with the proportion of these residues that belong to the Contact group.
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evu240-F6: Exposed Noncontact residues from COX I are much more conserved than expected from their destabilizing effect on the holoenzyme. The exposed residues from each mtDNA-encoded proteins were split into two groups: Contact (C) and noncontact (NC), according to the criteria given in the text. Afterwards, the ΣdN and mean ΔΔG were computed for each of these subsets. These two variables showed a significant negative correlation (n = 6, Pearson r = −0.774, P value = 0.035) that was improved when data corresponding to COX I Exposed Noncontact were excluded from the analysis (n = 5, Pearson r = −0.890, P value = 0.021). The inset shows the proportion of residues that have been described as functionally relevant among the Exposed Noncontact, in comparison with the proportion of these residues that belong to the Contact group.

Mentions: In an attempt to get further insight into the particular forces imposing such exceptionally high degree of conservation among Exposed Noncontact COX I residues (particularly within the Noninterface subset), we assessed the effect of in silico alanine scanning mutagenesis on the stability of the complex. Although the mean ΔΔG for Exposed Noncontact COX I residues (1.64 kJ/mol) was significantly higher than those values from COX II (1.20 kJ/mol) and COX III (1.16 kJ/mol), P values 0.015 and 0.008, respectively, the contribution of COX I Exposed Noncontact residues to the whole thermodynamic stability of the holoenzyme can hardly be invoked as a reason for their high degree of conservation, as it is evident from figure 6. For each mtDNA-encoded protein, the Contact and Exposed Noncontact subsets were employed to compute their ΣdN values, which were plotted against their corresponding ΔΔG mean values (fig. 6). We found a significant negative correlation between these two variables (P value = 0.035), indicating that those substitutions that tend to be more destabilizing are also more constrained, which is in line with our previous observations that thermodynamic stability plays a relevant role in the evolvability of mtDNA-encoded proteins (Aledo et al. 2012). However, the COX I Exposed Noncontact group showed up as an outlier. In this sense, for a ΔΔG of 1.64 kJ/mol (the mean value computed for COX I Exposed Noncontact residues) the expected ΣdN should be higher than twice the observed ΣdN (fig. 6). In other words, whatever the constraining forces may be, they seem to be unrelated to structural stability.Fig. 6.—


Protein-protein interfaces from cytochrome c oxidase I evolve faster than nonbinding surfaces, yet negative selection is the driving force.

Aledo JC, Valverde H, Ruíz-Camacho M, Morilla I, López FD - Genome Biol Evol (2014)

Exposed Noncontact residues from COX I are much more conserved than expected from their destabilizing effect on the holoenzyme. The exposed residues from each mtDNA-encoded proteins were split into two groups: Contact (C) and noncontact (NC), according to the criteria given in the text. Afterwards, the ΣdN and mean ΔΔG were computed for each of these subsets. These two variables showed a significant negative correlation (n = 6, Pearson r = −0.774, P value = 0.035) that was improved when data corresponding to COX I Exposed Noncontact were excluded from the analysis (n = 5, Pearson r = −0.890, P value = 0.021). The inset shows the proportion of residues that have been described as functionally relevant among the Exposed Noncontact, in comparison with the proportion of these residues that belong to the Contact group.
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getmorefigures.php?uid=PMC4255772&req=5

evu240-F6: Exposed Noncontact residues from COX I are much more conserved than expected from their destabilizing effect on the holoenzyme. The exposed residues from each mtDNA-encoded proteins were split into two groups: Contact (C) and noncontact (NC), according to the criteria given in the text. Afterwards, the ΣdN and mean ΔΔG were computed for each of these subsets. These two variables showed a significant negative correlation (n = 6, Pearson r = −0.774, P value = 0.035) that was improved when data corresponding to COX I Exposed Noncontact were excluded from the analysis (n = 5, Pearson r = −0.890, P value = 0.021). The inset shows the proportion of residues that have been described as functionally relevant among the Exposed Noncontact, in comparison with the proportion of these residues that belong to the Contact group.
Mentions: In an attempt to get further insight into the particular forces imposing such exceptionally high degree of conservation among Exposed Noncontact COX I residues (particularly within the Noninterface subset), we assessed the effect of in silico alanine scanning mutagenesis on the stability of the complex. Although the mean ΔΔG for Exposed Noncontact COX I residues (1.64 kJ/mol) was significantly higher than those values from COX II (1.20 kJ/mol) and COX III (1.16 kJ/mol), P values 0.015 and 0.008, respectively, the contribution of COX I Exposed Noncontact residues to the whole thermodynamic stability of the holoenzyme can hardly be invoked as a reason for their high degree of conservation, as it is evident from figure 6. For each mtDNA-encoded protein, the Contact and Exposed Noncontact subsets were employed to compute their ΣdN values, which were plotted against their corresponding ΔΔG mean values (fig. 6). We found a significant negative correlation between these two variables (P value = 0.035), indicating that those substitutions that tend to be more destabilizing are also more constrained, which is in line with our previous observations that thermodynamic stability plays a relevant role in the evolvability of mtDNA-encoded proteins (Aledo et al. 2012). However, the COX I Exposed Noncontact group showed up as an outlier. In this sense, for a ΔΔG of 1.64 kJ/mol (the mean value computed for COX I Exposed Noncontact residues) the expected ΣdN should be higher than twice the observed ΣdN (fig. 6). In other words, whatever the constraining forces may be, they seem to be unrelated to structural stability.Fig. 6.—

Bottom Line: Herein, using evolutionary data in combination with structural information of COX, we show that failing to discern the effects of interaction from other structural and functional effects can lead to deceptive conclusions such as the "optimizing hypothesis." Once spurious factors have been accounted for, data analysis shows that mtDNA-encoded residues engaged in contacts are, in general, more constrained than their noncontact counterparts.This differential behavior cannot be explained on the basis of predicted thermodynamic stability, as interactions between mtDNA-encoded subunits contribute more weakly to the complex stability than those interactions between subunits encoded by different genomes.Therefore, the higher conservation observed among mtDNA-encoded residues involved in intragenome interactions is likely due to factors other than structural stability.

View Article: PubMed Central - PubMed

Affiliation: Departamento de Biología Molecular y Bioquímica, Facultad de Ciencias, Universidad de Málaga, Spain caledo@uma.es.

Show MeSH