Molecular requirements for peroxisomal targeting of alanine-glyoxylate aminotransferase as an essential determinant in primary hyperoxaluria type 1.

[primary hyperoxaluria type 1]

Alanine-glyoxylate aminotransferase is a peroxisomal enzyme , of which various missense mutations lead to irreversible kidney damage via primary hyperoxaluria type 1 , in part caused by improper peroxisomal targeting . To unravel the molecular mechanism of its recognition by the peroxisomal receptor Pex 5 p , we have determined the crystal structure of the respective cargo-receptor complex . It shows an extensive protein /protein interface , with contributions from residues of the peroxisomal targeting signal 1 and additional loops of the C-terminal domain of the cargo . Sequence segments that are crucial for receptor recognition and hydrophobic core interactions within alanine-glyoxylate aminotransferase are overlapping , explaining why receptor recognition highly depends on a properly folded protein . We subsequently characterized several enzyme variants in vitro and in vivo and show that even minor protein fold perturbations are sufficient to impair Pex 5 p receptor recognition . We discuss how the knowledge of the molecular parameters for alanine-glyoxylate aminotransferase required for peroxisomal translocation could become useful for improved hyperoxaluria type 1 treatment .

Diseases
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Diseases presenting "subsequently characterized several enzyme variants in vitro" symptom

primary hyperoxaluria type 1

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