Disorders of peroxisome biogenesis

Braverman, Nancy; Dodt, Gabriele; Gould, Stephen J.; Valle, David

doi:10.1093/hmg/4.suppl_1.1791

Cited by 101 publications

(67 citation statements)

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“…The final constructs were sequence-verified. pVP Pex5S and pVP Pex5L were produced by cutting the vectors pPTS1-BP and pGAD424-pas10, respectively (38), with BglII, filling in the recessed ends with Klenow polymerase and then cutting out the insert with SalI. These inserts were purified and ligated into pVP16 (Clontech/BD Biosciences), which was cut with HindIII, then filled in with Klenow polymerase followed by a second restriction digest with SalI.…”

Section: Construct Descriptionmentioning

confidence: 99%

Peroxisomal Import of Human Alanine:glyoxylate Aminotransferase Requires Ancillary Targeting Information Remote from Its C Terminus

Huber

Birdsey

Lumb

et al. 2005

Journal of Biological Chemistry

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Although human alanine:glyoxylate aminotransferase (AGT) is imported into peroxisomes by a Pex5p-dependent pathway, the properties of its C-terminal tripeptide (KKL) are unlike those of any other type 1 peroxisomal targeting sequence (PTS1). We have previously suggested that AGT might possess ancillary targeting information that enables its unusual PTS1 to work. In this study, we have attempted to locate this information and to determine whether or not it is a characteristic of all vertebrate AGTs. Using the two-hybrid system, we show that human AGT interacts with human Pex5p in mammalian cells, but not yeast cells. Using (immuno)fluorescence microscopic analysis of the distribution of various constructs expressed in COS cells, we show the following. 1) The putative ancillary peroxisomal targeting information (PTS1A) in human AGT is located entirely within the smaller C-terminal structural domain of 110 amino acids, with the sequence between Val-324 and Ile-345 being the most likely candidate region. 2) The PTS1A is present in all mammalian AGTs studied (human, rat, guinea pig, rabbit, and cat), but not amphibian AGT (Xenopus). 3) The PTS1A is necessary for peroxisomal import of human, rabbit, and cat AGTs, but not rat and guinea pig AGTs. We speculate that the internal PTS1A of human AGT works in concert with the C-terminal PTS1 by interacting with Pex5p indirectly with the aid of a yet-to-be-identified mammal-specific adaptor molecule. This interaction might reshape the tetratricopeptide repeat domain allosterically, enabling it to accept KKL as a functional PTS1.Alanine:glyoxylate aminotransferase (AGT, 1 EC 2.6.1.44) catalyzes the transamination of the intermediary metabolite glyoxylate to glycine. A deficiency of AGT, as occurs in the hereditary disease primary hyperoxaluria type 1, allows glyoxylate to be oxidized to oxalate instead. The resulting increased synthesis and excretion of oxalate leads to the deposition of insoluble calcium oxalate in the kidney and urinary tract and, ultimately, renal failure (1). AGT is normally peroxisomal in human liver, but in a subset of primary hyperoxaluria type 1 patients it is mistargeted to mitochondria (2). Although the molecular basis of the peroxisome-to-mitochondrion mistargeting of AGT in primary hyperoxaluria type 1 has been subjected to extensive investigation (3-6), its normal targeting to peroxisomes has received much less attention (7,8).Peroxisomal import of human AGT is dependent on the presence of the type 1 peroxisomal targeting sequence (PTS1) receptor Pex5p, but not the PTS2 receptor Pex7p (7). However, several features of the peroxisomal targeting of AGT are unusual when compared with the targeting of other peroxisomal proteins. The C-terminal tripeptide of human AGT is KKL (9), which has a two-out-of-three match with the prototypical consensus PTS1 of (S/A/C)(K/R/H)(L/M) (10, 11). KKL is necessary for peroxisomal targeting of human AGT but insufficient to direct the peroxisomal targeting of reporter proteins, such as bacterial chloramphenicol acetyl...

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Section: Construct Descriptionmentioning

confidence: 99%

Peroxisomal Import of Human Alanine:glyoxylate Aminotransferase Requires Ancillary Targeting Information Remote from Its C Terminus

Huber

Birdsey

Lumb

et al. 2005

Journal of Biological Chemistry

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“…Presently, our knowledge on the structure/function of amino acid residues 118 -639 of mammalian Pex5p is quite vast. Indeed, a variety of biochemical and structural studies have shown that this region of the protein contains the binding site for PTS1-containing cargo proteins (7,(22)(23)(24)(25)(26)(27), seven Pex14p-binding domains (43)(44)(45), and binding sites for Pex7p (11)(12)(13)(14), Pex12p (46), and Pex13p (45). In sharp contrast, not much is known regarding the role of the first 117 amino acid residues of Pex5p.…”

Section: Pex5p Lacking the First 110 Amino Acid Residues Is Efficientmentioning

confidence: 99%

“…This peroxin recognizes a degenerated nona-peptide complying to the consensus sequence (R/K)(L/I/V)X 5 (H/Q)(L/A/F), the socalled peroxisomal targeting signal type 2 (PTS2) (8 -10). In mammals and plants, but not in lower eukaryotes, targeting of these PTS2-containing proteins seems to require Pex5p, suggesting that the two import pathways actually converge at the level of the PTS1 receptor (11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21).…”

mentioning

confidence: 99%

The N Terminus of the Peroxisomal Cycling Receptor, Pex5p, Is Required for Redirecting the Peroxisome-associated Peroxin Back to the Cytosol

Costa‐Rodrigues

Carvalho

Gouveia³

et al. 2004

Journal of Biological Chemistry

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Most newly synthesized peroxisomal matrix proteins are transported to the organelle by Pex5p, a remarkable multidomain protein involved in an intricate network of transient protein-protein interactions. Presently, our knowledge regarding the structure/function of amino acid residues 118 to the very last residue of mammalian Pex5p is quite vast. Indeed, the cargo-protein receptor domain as well as the binding sites for several peroxins have all been mapped to this region of Pex5p. In contrast, structural/functional data regarding the first 117 amino acid residues of Pex5p are still scarce. Here we show that a truncated Pex5p lacking the first 110 amino acid residues (⌬N110-Pex5p) displays exactly the peroxisomal import properties of the full-length peroxin implying that this N-terminal domain is involved neither in cargo-protein binding nor in the docking/translocation step of the Pex5p-cargo protein complex at the peroxisomal membrane. However, the ATP-dependent export step of ⌬N110-Pex5p from the peroxisomal membrane is completely blocked, a phenomenon that was also observed for a Pex5p version lacking just the first 17 amino acid residues but not for a truncated protein comprising amino acid residues 1-324 of Pex5p. By exploring the unique properties of ⌬N110-Pex5p, the effect of temperature on the import/export kinetics of Pex5p was characterized. Our data indicate that the export step of Pex5p from the peroxisomal compartment (in contrast with its insertion into the organelle membrane) is highly dependent on the temperature.

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“…The first PTS (PTS1) comprises a serine-lysine-leucine (SKL) sequence or one of its conservative variants located at the extreme carboxy-terminal end of the protein. The other PTS (PTS2) is less well defined, but available evidence suggests that the targeting information is contained within a stretch of 9 amino acids located near the amino-terminus of the polypeptide, with the amino acids at positions 1, 2, 8 and 9 being most important (Braverman et al 1995). Motley and coworkers (1994) have shown that the uptake of PTS1-containing proteins into peroxisomes is fully normal in RCDP, in contrast to the import of PTS2-containing proteins.…”

Section: Discussionmentioning

confidence: 99%

Phytanoyl‐CoA hydroxylase is not only deficient in classical Refsum disease but also in rhizomelic chondrodysplasia punctata

Jansen

Mihalik

Watkins

et al. 1997

J of Inher Metab Disea

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Disorders of peroxisome biogenesis

Cited by 101 publications

References 0 publications

Peroxisomal Import of Human Alanine:glyoxylate Aminotransferase Requires Ancillary Targeting Information Remote from Its C Terminus

Peroxisomal Import of Human Alanine:glyoxylate Aminotransferase Requires Ancillary Targeting Information Remote from Its C Terminus

The N Terminus of the Peroxisomal Cycling Receptor, Pex5p, Is Required for Redirecting the Peroxisome-associated Peroxin Back to the Cytosol

Phytanoyl‐CoA hydroxylase is not only deficient in classical Refsum disease but also in rhizomelic chondrodysplasia punctata

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