ArticlePloS one2013
The role of protein denaturation energetics and molecular chaperones in the aggregation and mistargeting of mutants causing primary hyperoxaluria type I.
Article in PloS one, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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Who cites it
21 citing papers in PubMed, 57 citations in OpenAlex.
- Impact of Ser81 phosphorylation on alanine: glyoxylate aminotransferase associated with Primary hyperoxaluria type I.Molecular biomedicine · 2026Article
- A Minor Haplotype Variant Determines the Pathogenicity of the p.Ile279Thr Substitution in the Primary Hyperoxaluria Type 1 Gene, AGXT.Journal of inherited metabolic disease · 2025Article
- Thermodynamic versus kinetic basis for the high conformational stability of nanobodies for therapeutic applications.FEBS letters · 2025Article
- Effect of the allelic background on the phenotype of primary hyperoxaluria type I.Current opinion in nephrology and hypertension · 2025Review
- Phosphorylation of Thr9 Affects the Folding Landscape of the N-Terminal Segment of Human AGT Enhancing Protein Aggregation of Disease-Causing Mutants.Molecules (Basel, Switzerland) · 2022Article
- Structural dynamics shape the fitness window of alanine:glyoxylate aminotransferase.Protein science : a publication of the Protein Society · 2022Article
- Perspectives in primary hyperoxaluria - historical, current and future clinical interventions.Nature reviews. Urology · 2022Review
- Dimerization Drives Proper Folding of Human Alanine:Glyoxylate Aminotransferase But Is Dispensable for Peroxisomal Targeting.Journal of personalized medicine · 2021Article
- Naturally-Occurring Rare Mutations Cause Mild to Catastrophic Effects in the Multifunctional and Cancer-Associated NQO1 Protein.Journal of personalized medicine · 2020Article
- Molecular basis of primary hyperoxaluria: clues to innovative treatments.Urolithiasis · 2019Review
- Review
- Translation inhibition corrects aberrant localization of mutant alanine-glyoxylate aminotransferase: possible therapeutic approach for hyperoxaluria.Journal of molecular medicine (Berlin, Germany) · 2018Article
- Molecular basis of classic galactosemia from the structure of human galactose 1-phosphate uridylyltransferase.Human molecular genetics · 2016Article
- Primary hyperoxalurias: diagnosis and treatment.Pediatric nephrology (Berlin, Germany) · 2015Review
- Molecular recognition of PTS-1 cargo proteins by Pex5p: implications for protein mistargeting in primary hyperoxaluria.Biomolecules · 2015Article
- S81L and G170R mutations causing Primary Hyperoxaluria type I in homozygosis and heterozygosis: an example of positive interallelic complementation.Human molecular genetics · 2014Article
- Insights into human phosphoglycerate kinase 1 deficiency as a conformational disease from biochemical, biophysical, and in vitro expression analyses.Journal of inherited metabolic disease · 2014Article
- Innovative strategies to treat protein misfolding in inborn errors of metabolism: pharmacological chaperones and proteostasis regulators.Journal of inherited metabolic disease · 2014Review
- Allele-specific characterization of alanine: glyoxylate aminotransferase variants associated with primary hyperoxaluria.PloS one · 2014Article
- Protein Stability, Folding and Misfolding in Human PGK1 Deficiency.Biomolecules · 2013Article
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Authors and funding
7 authors at 4 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Primary hyperoxaluria type I (PH1) is a conformational disease which result in the loss of alanine:glyoxylate aminotransferase (AGT) function. The study of AGT has important implications for protein folding and trafficking because PH1 mutants may cause protein aggregation and mitochondrial mistargeting. We herein describe a multidisciplinary study aimed to understand the molecular basis of protein aggregation and mistargeting in PH1 by studying twelve AGT variants. Expression studies in cell cultures reveal strong protein folding defects in PH1 causing mutants leading to enhanced aggregation, and in two cases, mitochondrial mistargeting. Immunoprecipitation studies in a cell-free system reveal that most mutants enhance the interactions with Hsc70 chaperones along their folding process, while in vitro binding experiments show no changes in the interaction of folded AGT dimers with the peroxisomal receptor Pex5p. Thermal denaturation studies by calorimetry support that PH1 causing mutants often kinetically destabilize the folded apo-protein through significant changes in the denaturation free energy barrier, whereas coenzyme binding overcomes this destabilization. Modeling of the mutations on a 1.9 Å crystal structure suggests that PH1 causing mutants perturb locally the native structure. Our work support that a misbalance between denaturation energetics and interactions with chaperones underlie aggregation and mistargeting in PH1, suggesting that native state stabilizers and protein homeostasis modulators are potential drugs to restore the complex and delicate balance of AGT protein homeostasis in PH1.
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