Different contribution of conserved amino acids to the global properties of triosephosphate isomerases

ABSTRACT It is generally assumed that the amino acids that exist in all homologous enzymes correspond to residues that participate in catalysis, or that are essential for folding and stability. Although this holds for catalytic residues, the function of conserved noncatalytic residues is not clear....

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Published in:Proteins, structure, function, and bioinformatics structure, function, and bioinformatics, 2014-02, Vol.82 (2), p.323-335
Main Authors: Aguirre, Yolanda, Cabrera, Nallely, Aguirre, Beatriz, Pérez-Montfort, Ruy, Hernandez-Santoyo, Alejandra, Reyes-Vivas, Horacio, Enríquez-Flores, Sergio, de Gómez-Puyou, Marietta Tuena, Gómez-Puyou, Armando, Sanchez-Ruiz, Jose M., Costas, Miguel
Format: Article
Language:English
Subjects:
Amino Acid Sequence
Amino Acid Substitution
Conserved Sequence
Crystallography, X-Ray
Entropy
Enzyme Stability
free-energy barriers
Giardia lamblia
Giardia lamblia - enzymology
homologous enzymes
Humans
kinetic stability
Kinetics
Models, Molecular
protein denaturation
Protein Unfolding
Protozoan Proteins - chemistry
Protozoan Proteins - genetics
Structural Homology, Protein
transition-state plasticity
Triose-Phosphate Isomerase - chemistry
Triose-Phosphate Isomerase - genetics
Trypanosoma brucei brucei - enzymology
Trypanosoma cruzi - enzymology
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Summary:ABSTRACT It is generally assumed that the amino acids that exist in all homologous enzymes correspond to residues that participate in catalysis, or that are essential for folding and stability. Although this holds for catalytic residues, the function of conserved noncatalytic residues is not clear. It is not known if such residues are of equal importance and have the same role in different homologous enzymes. In humans, the E104D mutation in triosephosphate isomerase (TIM) is the most frequent mutation in the autosomal diseases named “TPI deficiencies.” We explored if the E104D mutation has the same impact in TIMs from four different organisms (Homo sapiens, Giardia lamblia, Trypanosoma cruzi, and T. brucei). The catalytic properties were not significantly affected by the mutation, but it affected the rate and extent of formation of active dimers from unfolded monomers differently. Scanning calorimetry experiments indicated that the mutation was in all cases destabilizing, but the mutation effect on rates of irreversible denaturation and transition‐state energetics were drastically dependent on the TIM background. For instance, the E104D mutation produce changes in activation energy ranging from 430 kJ mol−1 in HsTIM to −78 kJ mol−1 in TcTIM. Thus, in TIM the role of a conserved noncatalytic residue is drastically dependent on its molecular background. Accordingly, it would seem that because each protein has a particular sequence, and a distinctive set of amino acid interactions, it should be regarded as a unique entity that has evolved for function and stability in the organisms to which it belongs. Proteins 2014; 82:323–335. © 2013 Wiley Periodicals, Inc.
ISSN:0887-3585
1097-0134
DOI:10.1002/prot.24398