Abstract
Author SummaryPeroxisomes are cell organelles contain proteins involved in various aspects of metabolism. Peroxisome proteins translocate from their site of synthesis in the cytoplasm across the organelle membrane in a fully folded and functional form. One such protein is the enzyme alanine–glyoxylate aminotransferase (AGT). It contains a targeting signal in its C-terminus that is recognized by a receptor protein, Pex5p, in the cytoplasm, which allows its subsequent translocation into the peroxisome. Mutations in AGT cause a disease known as primary hyperoxaluria type 1, in which patients suffer irreversible kidney damage; this disease results, in many cases, from improper targeting of AGT into peroxisomes. To understand better the mechanism of AGT import into peroxisomes and the molecular basis of this disease, we have determined the crystal structure of the complex between AGT and its receptor Pex5p. The structure reveals how overlapping segments of the protein sequence are crucial for both receptor recognition and maintaining the folded structure of the enzyme. Subsequently, we created and studied several mutants of the enzyme, including mutants that are known to cause disease, and found that even minor folding defects in the enzyme prevent its recognition by Pexp5 and its import into peroxisomes. Our data thus provide novel insights into the consequences of mutations in AGT on the catalytic activity of the enzyme, as well as into the mechanisms that cause primary hyperoxaluria type 1.
Highlights
Primary hyperoxaluria type 1 (PH1) is an autosomal recessive disorder that generally becomes symptomatic during childhood or adolescence and leads to renal failure, usually between the ages of 25 and 45 [1]
Human AGT consists of a 86 kDa homodimer and bears an atypical Lys-LysLeu (KKL) peroxisomal targeting signal 1 (PTS1) motif at its Cterminus, which is required for translocation of the enzyme into peroxisomes
One such protein is the enzyme alanine–glyoxylate aminotransferase (AGT). It contains a targeting signal in its C-terminus that is recognized by a receptor protein, Pex5p, in the cytoplasm, which allows its subsequent translocation into the peroxisome
Summary
Primary hyperoxaluria type 1 (PH1) is an autosomal recessive disorder that generally becomes symptomatic during childhood or adolescence and leads to renal failure, usually between the ages of 25 and 45 [1]. Several therapeutic options have been established, the only curative treatment to date is by liver-kidney transplantation [2]. PH1 is caused by functional deficiencies in the liver-specific, pyridoxaldependent enzyme alanine-glyoxylate aminotransferase (AGT, EC 2.6.1.44) [3]. AGT catalyzes the transamination of the peroxisomal intermediary metabolite glyoxylate to glycin. The absence of AGT in hepatic peroxisomes, owing to either dysfunction or mistargeting of AGT, causes glyoxylate to escape into the cytosol where it is further metabolized to oxalate and glycolate. The accumulation of oxalate—a compound that cannot be further metabolized in humans—leads to the progressive formation of insoluble calcium oxalate in the kidney and urinary tract, resulting in urolithiasis and/or nephrocalcinosis as the principal clinical manifestations
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