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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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(A) Crystal structure of HCAII (PDB ID 2CBA). Pro237 is highlighted by space-filling model; (B) Sequence alignment of CAII.
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f1-ijms-12-02797: (A) Crystal structure of HCAII (PDB ID 2CBA). Pro237 is highlighted by space-filling model; (B) Sequence alignment of CAII.

Mentions: Carbonic anhydrase (CA), a member of a large zinc metalloenzyme family, catalyzes the reversible reaction in which carbondioxide is hydrated into bicarbonate [15]. In higher vertebrates, there are several CA isoenzymes with dissimilar cellular and tissue distributions [15,16]. The deficiency of human CA II (HCAII) has been recognized to be associated with a disease called CAII deficiency syndrome (CADS) [17]. Particularly, the deficiency of HCAII can be caused by single-point mutations [16,18], which may severely affect HCAII catalytic properties and stability [4,5,19]. Among these mutations, the P237H mutation was found to significantly decrease the catalytic efficiency and stability of HCAII, suggesting that this mutation may lead to loss-of-function of HCAII and further result in HCAII deficiency [5]. P237 is located on the surface of the HCAII molecule (Figure 1), and is not involved in the active site or core structure of the enzyme. However, the dramatic decrease in the reduction of the Gibbs free energy of HCAII folding implied that it might be crucial to the correct packing of the adjacent secondary structures [5].


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

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

(A) Crystal structure of HCAII (PDB ID 2CBA). Pro237 is highlighted by space-filling model; (B) Sequence alignment of CAII.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f1-ijms-12-02797: (A) Crystal structure of HCAII (PDB ID 2CBA). Pro237 is highlighted by space-filling model; (B) Sequence alignment of CAII.
Mentions: Carbonic anhydrase (CA), a member of a large zinc metalloenzyme family, catalyzes the reversible reaction in which carbondioxide is hydrated into bicarbonate [15]. In higher vertebrates, there are several CA isoenzymes with dissimilar cellular and tissue distributions [15,16]. The deficiency of human CA II (HCAII) has been recognized to be associated with a disease called CAII deficiency syndrome (CADS) [17]. Particularly, the deficiency of HCAII can be caused by single-point mutations [16,18], which may severely affect HCAII catalytic properties and stability [4,5,19]. Among these mutations, the P237H mutation was found to significantly decrease the catalytic efficiency and stability of HCAII, suggesting that this mutation may lead to loss-of-function of HCAII and further result in HCAII deficiency [5]. P237 is located on the surface of the HCAII molecule (Figure 1), and is not involved in the active site or core structure of the enzyme. However, the dramatic decrease in the reduction of the Gibbs free energy of HCAII folding implied that it might be crucial to the correct packing of the adjacent secondary structures [5].

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