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The lower limits for protein stability and foldability in primary hyperoxaluria type I
Noel Mesa-Torres1, Eduardo Salido2, Angel L Pey1
1Departamento de Química-Física, Facultad de Ciencias, Universidad de Granada, E-18071 Granada, Spain.
Biochimica Et Biophysica Acta
|December 3, 2014
Summary
Mutations affect human alanine:glyoxylate aminotransferase (AGT) stability, impacting protein folding and primary hyperoxaluria type I (PH1) disease. Understanding AGT stability limits informs disease mechanisms and potential therapies.
Area of Science:
- Biochemistry
- Molecular Biology
- Protein Science
Background:
- Protein stability and foldability are crucial for understanding diseases like primary hyperoxaluria type I (PH1) and protein evolution.
- Alanine:glyoxylate aminotransferase (AGT) is an enzyme involved in glyoxylate detoxification, and its stability is critical for function.
Purpose of the Study:
- To comprehensively investigate the energetic basis of mutational effects on human AGT stability.
- To classify mutations based on their origin (natural or consensus) and their impact on kinetic stability.
Main Methods:
- Studied twenty-two AGT variants with kinetic stabilities spanning eleven orders of magnitude.
- Classified variants into naturally-occurring (including PH1 mutations) and consensus groups.
- Analyzed AGT dimer stability, denaturation rates, thermodynamic stability, and aggregation propensity.
Main Results:
- AGT dimer stability dictates denaturation rates.
- Mutations alter AGT stability through changes in thermodynamic stability and aggregation propensity of unfolded states.
- Identified two lower limits for AGT stability related to folding efficiency and in vivo glyoxylate detoxification.
Conclusions:
- The identified AGT stability limits help explain misfolding as a disease mechanism in PH1.
- Findings support the development of pharmacological ligands to enhance AGT stability as a therapeutic strategy for PH1.
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