Structural implications of a G170R mutation of alanine:glyoxylate aminotransferase that is associated with peroxisome-to-mitochondrion mistargeting

In a subset of patients with the hereditary kidney-stone disease primary hyperoxaluria type 1 (PH1), the liver-specific enzyme alanine: glyoxylate aminotransferase (AGT) is mistargeted from peroxisomes to mitochondria. This is a consequence of the combined presence of the common P11L polymorphism and a disease-specific G170R mutation. In this paper, the crystal structure of mutant human AGT containing the G170R replacement determined at a resolution of 2.6 angstrom is reported. The crystal structure of AGT consists of an intimate dimer in which an extended N-terminal segment of 21 amino acids from one subunit wraps as an elongated irregular coil around the outside of the crystallographic symmetry-related subunit. In addition to the N-terminal segment, the monomer structure contains a large domain of 261 amino acids and a small C-terminal domain of 110 amino acids. Comparison of the mutant AGT structure and that of wild-type normal AGT shows that the two structures are almost identical, with a backbone-atom r.m.s. deviation of 0.34 angstrom. However, evidence of significant local structural changes in the vicinity of the G170R mutation might be linked to the apparent decrease in protein stability.