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Impact of the 237th residue on the folding of human carbonic anhydrase II.

Wu MJ, Jiang Y, Yan YB - Int J Mol Sci (2011)

Bottom Line: Among the many mutations, the P237H mutation has been characterized to lead to a significant decrease in the activity of the enzyme and in the Gibbs free energy of folding.The FoldX theoretical calculations suggested that this residue did not significantly contribute to the overall folding of HCAII, since all mutants had small ΔΔG values (around 1 kcal/mol).The discrepancy between theoretical and experimental results suggested that caution should be taken when using the prediction methods to evaluate the details of disease-related mutations.

View Article: PubMed Central - PubMed

Affiliation: Key Laboratory of Bio-Resources and Eco-Environment of MOE, College of Life Science, Sichuan University, Chengdu 610064, China; E-Mail: wmj213@gmail.com.

ABSTRACT
The deficiency of human carbonic anhydrase II (HCAII) has been recognized to be associated with a disease called CAII deficiency syndrome (CADS). Among the many mutations, the P237H mutation has been characterized to lead to a significant decrease in the activity of the enzyme and in the Gibbs free energy of folding. However, sequence alignment indicated that the 237th residue of CAII is not fully conserved across all species. The FoldX theoretical calculations suggested that this residue did not significantly contribute to the overall folding of HCAII, since all mutants had small ΔΔG values (around 1 kcal/mol). The experimental determination indicated that at least three mutations affect HCAII folding significantly and the P237H mutation was the most deleterious one, suggesting that Pro237 was important to HCAII folding. The discrepancy between theoretical and experimental results suggested that caution should be taken when using the prediction methods to evaluate the details of disease-related mutations.

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Correlation between the FoldX prediction and the experimental measurements.
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f5-ijms-12-02797: Correlation between the FoldX prediction and the experimental measurements.

Mentions: Most mutations slightly destabilize both the N↔I and I↔U transitions except P- > A mutation seems to stabilize the N↔I transition. The ΔΔG values of folding were between 0.9 and 2.9 kcal/mol. The most destabilized mutation was P- > F, while the least was P- > I. This observation was quite different from the FoldX prediction, which indicated that HCAIIP237I was the most unstable and HCAIIP237F was the most stable mutant. The large discrepancy between the theoretical and experimental ΔΔG values for the three mutants HCAIIP237T, HCAIIP237F and HCAIIP237H (Figure 5) suggested that the effects of these mutations could not be predicted correctly. One possible reason is that the FoldX has a correlation coefficient of 0.81 and a standard deviation of 0.46 kcal/mol [20], and another may be that the prediction can give reasonable data of a large data set but not for the details of a small set, as indicated by other authors [32]. Nonetheless, the large experimental ΔΔG values (>2 kcal/mol) caused by the P237T, P237F and P237H mutations implied that the position 237 of CAII should play a role in CAII stability, and the disease-related mutation P237H was the most deleterious.


Impact of the 237th residue on the folding of human carbonic anhydrase II.

Wu MJ, Jiang Y, Yan YB - Int J Mol Sci (2011)

Correlation between the FoldX prediction and the experimental measurements.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC3116157&req=5

f5-ijms-12-02797: Correlation between the FoldX prediction and the experimental measurements.
Mentions: Most mutations slightly destabilize both the N↔I and I↔U transitions except P- > A mutation seems to stabilize the N↔I transition. The ΔΔG values of folding were between 0.9 and 2.9 kcal/mol. The most destabilized mutation was P- > F, while the least was P- > I. This observation was quite different from the FoldX prediction, which indicated that HCAIIP237I was the most unstable and HCAIIP237F was the most stable mutant. The large discrepancy between the theoretical and experimental ΔΔG values for the three mutants HCAIIP237T, HCAIIP237F and HCAIIP237H (Figure 5) suggested that the effects of these mutations could not be predicted correctly. One possible reason is that the FoldX has a correlation coefficient of 0.81 and a standard deviation of 0.46 kcal/mol [20], and another may be that the prediction can give reasonable data of a large data set but not for the details of a small set, as indicated by other authors [32]. Nonetheless, the large experimental ΔΔG values (>2 kcal/mol) caused by the P237T, P237F and P237H mutations implied that the position 237 of CAII should play a role in CAII stability, and the disease-related mutation P237H was the most deleterious.

Bottom Line: Among the many mutations, the P237H mutation has been characterized to lead to a significant decrease in the activity of the enzyme and in the Gibbs free energy of folding.The FoldX theoretical calculations suggested that this residue did not significantly contribute to the overall folding of HCAII, since all mutants had small ΔΔG values (around 1 kcal/mol).The discrepancy between theoretical and experimental results suggested that caution should be taken when using the prediction methods to evaluate the details of disease-related mutations.

View Article: PubMed Central - PubMed

Affiliation: Key Laboratory of Bio-Resources and Eco-Environment of MOE, College of Life Science, Sichuan University, Chengdu 610064, China; E-Mail: wmj213@gmail.com.

ABSTRACT
The deficiency of human carbonic anhydrase II (HCAII) has been recognized to be associated with a disease called CAII deficiency syndrome (CADS). Among the many mutations, the P237H mutation has been characterized to lead to a significant decrease in the activity of the enzyme and in the Gibbs free energy of folding. However, sequence alignment indicated that the 237th residue of CAII is not fully conserved across all species. The FoldX theoretical calculations suggested that this residue did not significantly contribute to the overall folding of HCAII, since all mutants had small ΔΔG values (around 1 kcal/mol). The experimental determination indicated that at least three mutations affect HCAII folding significantly and the P237H mutation was the most deleterious one, suggesting that Pro237 was important to HCAII folding. The discrepancy between theoretical and experimental results suggested that caution should be taken when using the prediction methods to evaluate the details of disease-related mutations.

Show MeSH
Related in: MedlinePlus