3R9A

Human alanine-glyoxylate aminotransferase in complex with the TPR domain of human PEX5P

Replaces:  3IMZ

Summary for 3R9A

• Entry DOI: 10.2210/pdb3r9a/pdb
• Descriptor: Serine--pyruvate aminotransferase, Peroxisomal targeting signal 1 receptor, 2-[BIS-(2-HYDROXY-ETHYL)-AMINO]-2-HYDROXYMETHYL-PROPANE-1,3-DIOL, ... (4 entities in total)
• Functional Keywords: tpr-domain, protein-protein complex, peroxisome, aminotransf pyruvate, transferase, disease mutation, membrane, peroxiso biogenesis disorder, protein transport, tpr repeat, transpo zellweger syndrome, transferase-transport protein complex, mitochondrion, pyridoxal phosphate, transferase/transport protein
• Biological source: Homo sapiens (human); More
• Cellular location: Peroxisome: P21549; Cytoplasm: P50542
• Total number of polymer chains: 4
• Total formula weight: 159308.73

Authors

Fodor, K.,Wilmanns, M. (deposition date: 2011-03-25, release date: 2011-05-11, Last modification date: 2012-05-02)

Primary citation

Fodor, K.,Wolf, J.,Erdmann, R.,Schliebs, W.,Wilmanns, M.
Molecular requirements for peroxisomal targeting of alanine-glyoxylate aminotransferase as an essential determinant in primary hyperoxaluria type 1
Plos Biol., 10:e1001309-e1001309, 2012

PubMed Abstract: 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 Pex5p, 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 Pex5p 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.

PubMed: 22529745
DOI: 10.1371/journal.pbio.1001309

Experimental method

X-RAY DIFFRACTION (2.35 Å)