Disease relevance of PEX13

• In humans, mutations in PEX13 can disrupt peroxisome biogenesis and lead to peroxisomal metabolic dysfunction and neurodegenerative disease [1].
• Therefore, we suggest that the active moiety of ZWS for the NF-kappaB activation has an endotoxin-like substance, that is abundantly observed in Gram-negative bacteria [2].
• Patients were divided into 4 etiological groups: Alcoholic cirrhosis (ALD) (38), Non-alcoholic cirrhosis (NALD) (35), non cirrhotic portal fibrosis (NCPF) (14) and extrahepatic portal vein obstruction (EHPVO) (14) [3].

High impact information on PEX13

• The SH3 domain of the Saccharomyces cerevisiae peroxisomal membrane protein Pex13p functions as a docking site for Pex5p, a mobile receptor for the import PTS1-containing proteins [4].
• In humans, mutations in the PEX13 gene, which encodes a peroxisomal membrane protein necessary for peroxisomal protein import, can lead to a Zellweger phenotype [5].
• Nonsense and temperature-sensitive mutations in PEX13 are the cause of complementation group H of peroxisome biogenesis disorders [6].
• Expression of human PEX13 cDNA restored peroxisome assembly in ZP128 and ZP150 [7].
• Mutation in PEX13 of mutant ZP150 was determined by RT-PCR: G to A transition resulted in one amino acid substitution, Ser319Asn, in one allele and truncation of a 42 amino acid sequence from Asp265 to Lys306 in another allele [7].

Biological context of PEX13

• As such, mutations in PEX13 would be expected to abrogate peroxisomal protein import and result in PBD phenotypes [8].
• PEX13 spans approximately 11 kb on chromosome 2 and contains four exons, one more than previously thought [8].
• A more mildly affected NALD patient (H-01), whose fibroblasts showed the temperature-sensitive (TS) phenotype, was homozygous for a missense mutation in the SH3 domain of Pex13p, I326T [6].
• The Src homology 3 (SH3) domain-containing peroxisomal membrane protein Pex13p is an essential component of the import machinery for matrix proteins and forms a binding site for the peroxisomal targeting type I (PTS1) receptor Pex5p [9].

Anatomical context of PEX13

• We examined the ability of PEX13 expression to rescue the peroxisomal protein import defects of fibroblast cells representing all known PBD complementation groups [8].
• Therefore, ZP128 and ZP150 are CHO cell lines with a phenotype of impaired PEX13 [7].
• The strong interaction of Pex5p with the membrane of the organelle is not affected by mild protease treatment of intact organelles, conditions that result in the partial degradation of Pex13p [10].

Associations of PEX13 with chemical compounds

• Alanine-scanning analysis of the highly conserved seven (six in Pex5pS) pentapeptide WXXXF/Y motifs residing at the N-terminal region indicated that these motifs were essential for the interaction of Pex5p with Pex14p and Pex13p [11].
• ZWS activity was decreased by treatment with polymyxin B, but not with lysozyme and zymolyase [2].

Physical interactions of PEX13

• PEX13 protein has an SH3 docking site that binds to the PTS-1 receptor [12].
• Furthermore, we detected the Pex13p complexes likewise formed with Pex5pL-bound Pex7p-PTS2 proteins [13].
• Here we demonstrate that a mutant of Pex13p that fails to bind to Pex19p nevertheless targets to and integrates into the peroxisomal membrane [14].

Other interactions of PEX13

• We have previously reported the identification of human PEX13, the gene encoding the docking factor for the PTS1 receptor, or PEX5 protein [8].
• Genomic structure of PEX13, a candidate peroxisome biogenesis disorder gene [8].
• Import of matrix proteins into peroxisomes requires two targeting signal-specific import receptors, Pex5p and Pex7p, and their binding partners at the peroxisomal membrane, Pex13p and Pex14p [15].
• Localization to peroxisomes of membrane proteins such as Pex14p, Pex13p, and PMP70 was interfered with in CHO-K1 cells by a higher level expression of the pex16 patient-derived dysfunctional but topogenically active Pex16pR176ter comprising resides 1-176 or of the C-terminal cytoplasmic part starting from residues at 244 to the C terminus [16].
• Pex5p carrying the cargos, PTS1 and PTS2, docks with the initial site Pex14p in a putative import machinery, subsequently translocating to other components such as Pex13p, Pex2p, Pex10p and Pex12p, whereby the matrix proteins are imported [17].

Analytical, diagnostic and therapeutic context of PEX13

• To further examine the molecular mechanism underlying this competition, six evolutionarily conserved amino acids in the Pex5p/Pex13p/Pex19p binding domain of Pex14p were subjected to site-directed mutagenesis and the corresponding mutants functionally analyzed [14].

References