Disease relevance of PEX19

• The human Pex19p cDNA was overexpressed in Escherichia coli, and a highly purified sample of the Pex19p protein was prepared [1].
• The aims of this study were to evaluate the effect of PXF (1600 mg daily) in diabetic patients with intermittent claudication [2].
• In conclusion PXF is effective and cost-effective in improving ulcer healing in patients with chronic venous hypertension [3].
• METHODS: In this retrospective study, 56 eyes from 44 patients with primary open angle glaucoma, ocular hypertension, pseudo-exfoliative (PXF) or pigment dispersion glaucoma (PDG) were included [4].
• The aim of this study was to evaluate PXF (pentoxifylline; 1600 mg daily vs placebo) in patients with retinal vein thrombosis (RVT) in a 4-week trial, evaluating clinical outcome and retinal flow [5].

High impact information on PEX19

• Both human and yeast cells lacking peroxisomes due to mutations in PEX3 or PEX19 genes regenerate the organelles upon reintroduction of the corresponding wild-type version [6].
• PEX3 functions as a PEX19 docking factor in the import of class I peroxisomal membrane proteins [7].
• PEX19 binds these PMPs in the cytoplasm and delivers them to the peroxisome for subsequent insertion into the peroxisome membrane, indicating that there may be a PEX19 docking factor in the peroxisome membrane [7].
• Here, we demonstrate that PEX19 binds and stabilizes newly synthesized PMPs in the cytosol, binds to multiple PMP targeting signals (mPTSs), interacts with the hydrophobic domains of PMP targeting signals, and is essential for PMP targeting and import [8].
• In addition, we demonstrate that PEX19, a factor required for peroxisomal membrane biogenesis, interacts with the two minimal targeting regions of PMP34 [9].

Biological context of PEX19

• We predicted in human peroxisomal membrane proteins (PMPs) the binding sites for PEX19, a key player in the topogenesis of PMPs, by virtue of an algorithm developed for yeast PMPs [10].
• The finding that the protein derived from the splice variant lacking D3 is able to interact with several peroxisomal membrane proteins and to restore peroxisomal biogenesis challenges the previous assumption that farnesylation of PEX19 is essential for its biological functionality [11].
• The farnesylation consensus motif CLIM is located in the PEX19 domain D3 [11].
• Functional complementation studies in PEX19-deficient human fibroblasts revealed that transfection of PEX19DeltaE8-cDNA leads to restoration of both peroxisomal membranes and of functional peroxisomes, whereas transfection of PEX19DeltaE2-cDNA does not restore peroxisomal biogenesis [11].
• Interaction of PEX3 and PEX19 visualized by fluorescence resonance energy transfer (FRET) [12].

Anatomical context of PEX19

• We corroborated the requirement of the ALDP PEX19-binding site for peroxisomal targeting in human fibroblasts and showed that the minimal ALDP fragment targets correctly also in yeast, again in a PEX19-binding site-dependent manner [10].
• Pex19p was partly localized to peroxisomes but mostly localized in the cytosol [13].
• This hypothesis is supported by the observation that the loss of PEX19 results in degradation of PMPs and/or mislocalization of PMPs to the mitochondrion [14].
• Identification of trypanosomatid PEX19: functional characterization reveals impact on cell growth and glycosome size and number [15].
• Western blot analysis indicates that PEX19 is located in the cytosolic and brush-border membrane fractions (microvilli and the subapical component) [16].

Associations of PEX19 with chemical compounds

• One PEX19-binding site overlapped with the TMD, the other was contained within the luminal domain [17].
• Evidence is provided that farnesylation of Pex19p takes place at the cysteine of the C-terminal CKQQ amino acid sequence [18].
• Stress chaperones, mortalin, and pex19p mediate 5-aza-2' deoxycytidine-induced senescence of cancer cells by DNA methylation-independent pathway [19].
• Treatment with placebo or pentoxifylline (PXF; 400 mg, 3 times daily) lasted 6 months and was associated to elastic bandaging [3].

Physical interactions of PEX19

• Finally, our observation that Pex19p contains two distinct binding sites for Pex3p suggests that the peroxin may bind PMPs in multiple places and for multiple purposes [20].
• Interestingly, the identified PEX19-binding site of ALDP coincided with its previously determined targeting motif [10].
• PEX19 does not specifically bind to the targeting elements of human PMP70 [21].
• In yeast two-hybrid assays, Pex10p and Pex11pbeta interacted only with full-length Pex19p [13].
• Human adrenoleukodystrophy protein and related peroxisomal ABC transporters interact with the peroxisomal assembly protein PEX19p [22].

Regulatory relationships of PEX19

• To address this question by fluorescence resonance energy transfer (FRET) analysis, we engineered the enhanced yellow fluorescent protein (EYFP) to the C-terminus of PEX3 and the enhanced cyan fluorescent protein (ECFP) to the N-terminus of PEX19 [23].

Other interactions of PEX19

• PEX3, PEX16 and PEX19 are considered to be required for the early stage of peroxisome biogenesis [24].
• Alternatively, Pex19p might act as a multifunctional peroxin and participate in a number of these activities [20].
• Human PEX19: cDNA cloning by functional complementation, mutation analysis in a patient with Zellweger syndrome, and potential role in peroxisomal membrane assembly [25].
• A highly conserved N-terminal region, encompassing residues 21-70, interacts with the PTS1 receptor Pex5p, Pex13p, and Pex19p that is essential for membrane biogenesis [26].
• 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 [27].

Analytical, diagnostic and therapeutic context of PEX19

• To identify the regions that interact with Pex19p, various truncated PMP70 were translated in the presence of Pex19p and subjected to co-immunoprecipitation [28].

References