2YOB

High resolution AGXT_M structure

Summary for 2YOB

• Entry DOI: 10.2210/pdb2yob/pdb
• Related: 1H0C 1J04
• Descriptor: SERINE--PYRUVATE AMINOTRANSFERASE, PYRIDOXAL-5'-PHOSPHATE, 2-[BIS-(2-HYDROXY-ETHYL)-AMINO]-2-HYDROXYMETHYL-PROPANE-1,3-DIOL, ... (6 entities in total)
• Functional Keywords: transferase, primary hyperoxaluria type i, agxt folding and stability defects
• Biological source: HOMO SAPIENS (HUMAN)
• Cellular location: Peroxisome: P21549
• Total number of polymer chains: 2
• Total formula weight: 86623.59

Authors

Fabelo-Rosa, I.,Mesa-Torres, N.,Riverol, D.,Yunta, C.,Albert, A.,Salido, E.,Pey, A.L. (deposition date: 2012-10-22, release date: 2013-10-30, Last modification date: 2023-12-20)

Primary citation

Mesa-Torres, N.,Fabelo-Rosa, I.,Riverol, D.,Yunta, C.,Albert, A.,Salido, E.,Pey, A.L.
The Role of Protein Denaturation Energetics and Molecular Chaperones in the Aggregation and Mistargeting of Mutants Causing Primary Hyperoxaluria Type I
Plos One, 8:71963-, 2013

PubMed 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.

PubMed: 24205397
DOI: 10.1371/JOURNAL.PONE.0071963

Experimental method

X-RAY DIFFRACTION (1.9 Å)