| Structural highlights
Disease
[PEX14_HUMAN] Zellweger syndrome;Neonatal adrenoleukodystrophy;Infantile Refsum disease. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. [PEX5_HUMAN] Defects in PEX5 are the cause of peroxisome biogenesis disorder 2A (PBD2A) [MIM:214110]. A fatal peroxisome biogenesis disorder belonging to the Zellweger disease spectrum and characterized clinically by severe neurologic dysfunction with profound psychomotor retardation, severe hypotonia and neonatal seizures, craniofacial abnormalities, liver dysfunction, and biochemically by the absence of peroxisomes. Additional features include cardiovascular and skeletal defects, renal cysts, ocular abnormalities, and hearing impairment. Most severely affected individuals with the classic form of the disease (classic Zellweger syndrome) die within the first year of life.[1] Defects in PEX5 are the cause of peroxisome biogenesis disorder 2B (PBD2B) [MIM:202370]. A peroxisome biogenesis disorder that includes neonatal adrenoleukodystrophy (NALD) and infantile Refsum disease (IRD), two milder manifestations of the Zellweger disease spectrum. The clinical course of patients with the NALD and IRD presentation is variable and may include developmental delay, hypotonia, liver dysfunction, sensorineural hearing loss, retinal dystrophy and vision impairment. Children with the NALD presentation may reach their teens, while patients with the IRD presentation may reach adulthood. The clinical conditions are often slowly progressive in particular with respect to loss of hearing and vision. The biochemical abnormalities include accumulation of phytanic acid, very long chain fatty acids (VLCFA), di- and trihydroxycholestanoic acid and pipecolic acid.
Function
[PEX14_HUMAN] Component of the peroxisomal translocation machinery with PEX13 and PEX17. Interacts with both the PTS1 and PTS2 receptors. Binds directly to PEX17. [PEX5_HUMAN] Binds to the C-terminal PTS1-type tripeptide peroxisomal targeting signal (SKL-type) and plays an essential role in peroxisomal protein import.[2] [3] [4]
Publication Abstract from PubMed
Protein import into peroxisomes relies on the import receptor Pex5, which recognizes proteins with a peroxisomal targeting signal 1 (PTS1) in the cytosol and directs them to a docking complex at the peroxisomal membrane. Receptor-cargo docking occurs at the membrane-associated protein Pex14. In human cells, this interaction is mediated by seven conserved diaromatic pentapeptide motifs (WxxxF/Y-motifs) in the N-terminal half of Pex5 and the N-terminal domain (NTD) of Pex14. A systematic screening of a Pex5-peptide library by ligand blot analysis revealed a novel Pex5-Pex14 interaction site of Pex5. The novel motif comprises the sequence LVAEF with the evolutionary conserved consensus sequence LVxEF. Replacement of the amino acids LVAEF sequence by alanines strongly affects matrix protein import into peroxisomes in vivo. The NMR structure of a complex of Pex5-(57-71) with Pex14-NTD showed that the novel motif binds in a similar alpha-helical orientation as the WxxxF/Y motif but that the tryptophan pocket is now occupied by a leucine residue. Surface plasmon resonance analyses revealed 33-times faster dissociation rates for the LVxEF ligand when compared to a WxxxF/Y motif. Surprisingly, substitution of the novel motif with the higher affinity WxxxF/Y motif impairs protein import into peroxisomes. These data indicate that the distinct kinetic properties of the novel Pex14-binding site in Pex5 are important for processing of the PTS1 receptor at the peroxisomal membrane. The novel Pex14 binding site may represent the initial tethering site of Pex5 from which the cargo-loaded receptor is further processed in a sequential manner.
A novel Pex14 interacting site of human Pex5 is critical for matrix protein import into peroxisomes.,Neuhaus A, Kooshapur H, Wolf J, Meyer HN, Madl T, Saidowsky J, Hambruch E, Lassam A, Jung M, Sattler M, Schliebs W, Erdmann R J Biol Chem. 2013 Nov 14. PMID:24235149[5]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Dodt G, Braverman N, Wong C, Moser A, Moser HW, Watkins P, Valle D, Gould SJ. Mutations in the PTS1 receptor gene, PXR1, define complementation group 2 of the peroxisome biogenesis disorders. Nat Genet. 1995 Feb;9(2):115-25. PMID:7719337 doi:http://dx.doi.org/10.1038/ng0295-115
- ↑ Dodt G, Braverman N, Wong C, Moser A, Moser HW, Watkins P, Valle D, Gould SJ. Mutations in the PTS1 receptor gene, PXR1, define complementation group 2 of the peroxisome biogenesis disorders. Nat Genet. 1995 Feb;9(2):115-25. PMID:7719337 doi:http://dx.doi.org/10.1038/ng0295-115
- ↑ Wiemer EA, Nuttley WM, Bertolaet BL, Li X, Francke U, Wheelock MJ, Anne UK, Johnson KR, Subramani S. Human peroxisomal targeting signal-1 receptor restores peroxisomal protein import in cells from patients with fatal peroxisomal disorders. J Cell Biol. 1995 Jul;130(1):51-65. PMID:7790377
- ↑ Fransen M, Brees C, Baumgart E, Vanhooren JC, Baes M, Mannaerts GP, Van Veldhoven PP. Identification and characterization of the putative human peroxisomal C-terminal targeting signal import receptor. J Biol Chem. 1995 Mar 31;270(13):7731-6. PMID:7706321
- ↑ Neuhaus A, Kooshapur H, Wolf J, Meyer HN, Madl T, Saidowsky J, Hambruch E, Lassam A, Jung M, Sattler M, Schliebs W, Erdmann R. A novel Pex14 interacting site of human Pex5 is critical for matrix protein import into peroxisomes. J Biol Chem. 2013 Nov 14. PMID:24235149 doi:http://dx.doi.org/10.1074/jbc.M113.499707
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