Identification of mutations associated with peroxisome-to-mitochondrion mistargeting of alanine/glyoxylate aminotransferase in primary hyperoxaluria type 1.

Purdue, P. Edward; Takada, Yoshikazu; Danpure, Christopher J.

doi:10.1083/jcb.111.6.2341

Cited by 220 publications

(183 citation statements)

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“…One such example is provided in the medical condition known as primary hyperoxaluria type 1. About 40% of the cases of primary hyperoxaluria type 1 are caused by mistargeting of the enzyme alanine-glyoxylate aminotransferase from peroxisomes to mitochondria as a result of at least two mutations (33). Wild-type alanine-glyoxylate aminotransferase forms a stable homodimer in the cell (33) with a cryptic N-terminal mitochondrial targeting sequence and a functional C-terminal nonconsensus type 1 peroxisomal targeting sequence (34).…”

Section: Discussionmentioning

confidence: 99%

Effect of protein structure on mitochondrial import

Wilcox

Choy

Bustamante

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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Most proteins that are to be imported into the mitochondrial matrix are synthesized as precursors, each composed of an Nterminal targeting sequence followed by a mature domain. Precursors are recognized through their targeting sequences by receptors at the mitochondrial surface and are then threaded through import channels into the matrix. Both the targeting sequence and the mature domain contribute to the efficiency with which proteins are imported into mitochondria. Precursors must be in an unfolded conformation during translocation. Mitochondria can unfold some proteins by changing their unfolding pathways. The effectiveness of this unfolding mechanism depends on the local structure of the mature domain adjacent to the targeting sequence. This local structure determines the extent to which the unfolding pathway can be changed and, therefore, the unfolding rate increased. Atomic force microscopy studies find that the local structures of proteins near their N and C termini also influence their resistance to mechanical unfolding. Thus, protein unfolding during import resembles mechanical unfolding, and the specificity of import is determined by the resistance of the mature domain to unfolding as well as by the properties of the targeting sequence.protein unfolding ͉ mitochondria ͉ protein import ͉ protein sorting ͉ atomic force microscopy

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Section: Discussionmentioning

confidence: 99%

Effect of protein structure on mitochondrial import

Wilcox

Choy

Bustamante

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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“…Val 326 3 Ile segregates with a variant called the minor (African) AGXT allele (43). Although the functional effects of the two PTS1A polymorphisms have not been well characterized, it is known that Ile 340 3 Met can partially counteract the untoward effects of the Pro 11 3 Leu polymorphism, which include partial mistargeting, slowing down dimerization, and decreasing specific catalytic activity (3,44). In some of the mammals discussed in this report (i.e.…”

Section: Cell Context Dependence Of the Interaction Between Humanmentioning

confidence: 99%

“…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)(4)(5)(6), its normal targeting to peroxisomes has received much less attention (7,8).…”

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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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“…1 Cases have also been identified in subjects suffering from HIV, early cytomegalovirus (CMV) retinitis, and systemic herpes simplex virus (HSV) infection. 2,3 Case report A 37-year-old man with HIV and CMV þ, after 9 weeks of treatment with highly active antiretroviral therapy (HAART) for acute retinal necrosis in OS, was referred for a mild visual acuity (VA) loss in OD (from 20/20 to 20/25). At fundus examination, he presented a perivascular creamy sheathing of retinal veins in the whole vascular net (Figure 1a1Àa2).…”

Section: Discussionmentioning

confidence: 99%

“…2 Eye involvement in primary hyperoxaluria consists of calcium oxalate deposits at the level of the retinal pigment epithelium (RPE) with surrounding areas of hypertrophic and hyperplastic RPE. 1,3 Some authors reported on unusual intraretinal distribution of oxalate deposits, apparently sparing the RPE (studies carried out on ocular tissues obtained at autopsy).…”

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confidence: 99%