Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:6.3.2.19 (ubiquitin-protein ligase)
799 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mutation of the parkin gene, which encodes an E3 ubiquitin-protein ligase, is the major cause of autosomal recessive juvenile parkinsonism (ARJP). Although various substrates for parkin have been identified, the mechanisms that regulate the ubiquitin ligase activity of parkin are poorly understood. Here we report that 14-3-3eta, a chaperone-like protein present abundantly in neurons, could bind to parkin and negatively regulate its ubiquitin ligase activity. Furthermore, 14-3-3eta could bind to the linker region of parkin but not parkin with ARJP-causing R42P, K161N, and T240R mutations. Intriguingly, alpha-synuclein (alpha-SN), another familial Parkinson's disease (PD) gene product, abrogated the 14-3-3eta-induced suppression of parkin activity. alpha-SN could bind tightly to 14-3-3eta and consequently sequester it from the parkin-14-3-3eta complex. PD-causing A30P and A53T mutants of alpha-SN could not bind 14-3-3eta, and failed to activate parkin. Our findings indicate that 14-3-3eta is a regulator that functionally links parkin and alpha-SN. The alpha-SN-positive and 14-3-3eta-negative control of parkin activity sheds new light on the pathophysiological roles of parkin.
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PMID:14-3-3eta is a novel regulator of parkin ubiquitin ligase. 1609 43

Parkinson disease (PD) is a common neurodegenerative disorder, which involves the deterioration of dopaminergic neurons in the pars compacta of the substantia nigra. The etiology of PD is still unknown, but recent identification of mutations in familial cases of PD has advanced the understanding of the molecular mechanisms of this neurological disease. Mutations in the parkin gene, which encodes for ubiquitin-protein ligase (E3), have been implicated in autosomal recessive juvenile Parkinsonism, an early onset and common familial form of PD. Here we reported that Parkin selectively binds to RanBP2, which is localized in the cytoplasmic filament of the nuclear pore complex and belongs to the small ubiquitin-related modifier E3 ligase family. We also demonstrated that RanBP2 becomes a target for Parkin E3 ubiquitin-ligase and is processed via Parkin-mediated ubiquitination and subsequent proteasomal degradation. Furthermore, Parkin controls the intracellular levels of sumoylated HDAC4, as a result of the ubiquitination and degradation of RanBP2. Our findings suggested that the intracellular levels of RanBP2 and its functional activity may be modulated by Parkin-mediated ubiquitination and proteasomal pathways.
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PMID:Parkin ubiquitinates and promotes the degradation of RanBP2. 1633 88

Mutations in the parkin gene, encoding an E3 ubiquitin-protein ligase, are a frequent cause of autosomal recessive parkinsonism and are also involved in sporadic Parkinson's disease. Loss of Parkin function is thought to compromise the polyubiquitylation and proteasomal degradation of specific substrates, leading to their deleterious accumulation. Several studies have analyzed the effects of parkin gene mutations on the biochemical properties of the protein. However, the absence of a cell-free system for studying intrinsic Parkin activity has limited the interpretation of these studies. Here we describe the biochemical characterization of Parkin and 10 pathogenic variants carrying amino-acid substitutions throughout the sequence. Mutations in the RING fingers or the ubiquitin-like domain decreased the solubility of the protein in detergent and increased its tendency to form visible aggregates. None of the mutations studied compromised the binding of Parkin to a series of known protein partners/substrates. Moreover, only two variants with substitutions of conserved cysteine residues of the second RING finger were inactive in a purely in vitro ubiquitylation assay, demonstrating that loss of ligase activity is a minor pathogenic mechanism. Interestingly, in this in vitro assay, Parkin catalyzed the linkage of single ubiquitin molecules only, whereas the ubiquitin-protein ligases CHIP and Mdm2 promoted the formation of polyubiquitin chains. Similarly, in mammalian cells Parkin promoted the multimonoubiquitylation of its substrate p38, rather than its polyubiquitylation. Thus, Parkin may mediate polyubiquitylation or proteasome-independent monoubiquitylation depending on the protein context. The discovery of monoubiquitylated Parkin species in cells hints at a novel post-translational modification potentially involved in the regulation of Parkin function.
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PMID:Biochemical analysis of Parkinson's disease-causing variants of Parkin, an E3 ubiquitin-protein ligase with monoubiquitylation capacity. 1671

There are growing lines of evidence addressing the importance of the ubiquitin-proteasome system (UPS) that catalyzes various biological reactions rapidly, methodically, exhaustively, and unidirectionally. UPS is responsible for a diverse array of biologically important cellular processes, such as cell-cycle progression, signaling cascades and developmental programs. This system is also involved in the protein quality control, which maintains the homeostasis of the cell. Of particular interest is that UPS provides a clue for understanding of the molecular mechanisms underlying various neurodegenerative diseases. In the last decade, we witnessed a tremendous progress in uncovering the mechanisms of Parkinson's disease (PD). Of the several genes that can cause familial PD, parkin, the causative gene of autosomal recessive juvenile parkinsonism (AR-JP), is of a special interest because it encodes an ubiquitin-protein ligase, which covalently attaches ubiquitin to target proteins, designating them for destruction by the proteasome (a eukaryotic ATP-dependent protease complex). This review summarizes recent studies on the UPS pathway with a special reference to parkin, focusing on how parkin is linked to the pathogenesis of AR-JP.
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PMID:[Impairment of the ubiquitin-proteasome system and neurodegeneration]. 1672 63

Parkin is a protein encoded by the corresponding parkin gene. It exhibits ubiquitin-protein ligase activity. In this review, we analyze domain structure, substrate specificity, subcellular localization of parkin, and regulation of its activity. Then we discuss data on the effects of various mutations in the parkin gene on structure and functions of this protein and results obtained with parkin knock-out animals. Better understanding of parkin biochemistry, its compartmentalization, functions, and altered functions would help the development of new approaches for the treatment of both inherited and sporadic cases of Parkinson's disease.
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PMID:Ubiquitin-protein ligase parkin and its role in the development of Parkinson's disease. 1697 47

Parkinson's Disease (PD) is a common neurodegenerative disorder that is characterized by the progressive loss of dopamine (DA) neurons. Accompanying the loss the of DA neurons is the accumulation of Lewy bodies and neurites, intracytoplasmic proteinaceous inclusions that contain alpha-synuclein, synphilin-1, components of the ubiquitin proteasomal pathway and parkin. Recent advances indicate that PD is due in some individuals to genetic mutations in alpha-synuclein, DJ-1, PINK-1, LRRK2, and parkin. Understanding the molecular mechanisms by which mutations in familial-linked genes cause PD holds great promise for unraveling the mechanisms by which DA neurons degenerate in PD. Parkin is E3-ubiquitin-protein ligase that ubiquitinates itself and promotes its own degradation. Familial associated mutations of parkin have impaired ubiquitin ligase function suggesting that this may be the cause of familial autosomal recessive PD. Parkin might be required for formation of Lewy bodies as Lewy bodies are absent in patients with parkin mutations. Parkin interacts with and ubiquitinates the alpha-synuclein interacting protein, synphilin-1. Formation of Lewy-body-like ubiquitin-positive cytosolic inclusions occurs upon coexpression of alpha-synuclein, synphilin-1 and parkin. Nitric oxide inhibits Parkin's E-3 ligase activity and its protective function by nitric oxide through S-nitrosylation both in vitro and in vivo. Nitrosative and oxidative stress link parkin function with the more common sporadic form of Parkinson's disease and the related alpha-synucleinopathy, DLBD. Development of new therapies for PD and other disorders associated with nitrosative and oxidative stress may follow the elucidation of the pathways by which NO S-nitrosylates and inhibits parkin. Moreover, parkin and alpha-synuclein are linked in common pathogenic mechanism through their interaction with synphilin-1 and parkin may be important for the formation of Lewy bodies.
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PMID:Parkin and defective ubiquitination in Parkinson's disease. 1701 31

Selective loss of dopaminergic neurons is the final common pathway in Parkinson's disease. Expression of Parkin associated endothelin-receptor like receptor (Pael-R) in mouse brain was achieved by injecting adenoviral vectors carrying a modified neuron-specific promoter and Cre recombinase into the striatum. Upregulation of Pael-R in the substantia nigra pars compacta of mice by retrograde infection induced endoplasmic reticulum (ER) stress leads to death of dopaminergic neurons. The role of ER stress in dopaminergic neuronal vulnerability was highlighted by their decreased survival in mice deficient in the ubiquitin-protein ligase Parkin and the ER chaperone ORP150 (150 kDa oxygen-regulated protein). Dopamine-related toxicity was also a key factor, as a dopamine synthesis inhibitor blocked neuronal death in parkin null mice. These data suggest a model in which ER- and dopamine-related stress are major contributors to decreased viability of dopaminergic neurons in a setting relevant to Parkinson's disease.
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PMID:Pael receptor induces death of dopaminergic neurons in the substantia nigra via endoplasmic reticulum stress and dopamine toxicity, which is enhanced under condition of parkin inactivation. 1711 40

Loss-of-function mutations in the PTEN-induced kinase 1 (PINK1) or parkin genes, which encode a mitochondrially localized serine/threonine kinase and a ubiquitin-protein ligase, respectively, result in recessive familial forms of Parkinsonism. Genetic studies in Drosophila indicate that PINK1 acts upstream of Parkin in a common pathway that influences mitochondrial integrity in a subset of tissues, including flight muscle and dopaminergic neurons. The mechanism by which PINK1 and Parkin influence mitochondrial integrity is currently unknown, although mutations in the PINK1 and parkin genes result in enlarged or swollen mitochondria, suggesting a possible regulatory role for the PINK1/Parkin pathway in mitochondrial morphology. To address this hypothesis, we examined the influence of genetic alterations affecting the machinery that governs mitochondrial morphology on the PINK1 and parkin mutant phenotypes. We report that heterozygous loss-of-function mutations of drp1, which encodes a key mitochondrial fission-promoting component, are largely lethal in a PINK1 or parkin mutant background. Conversely, the flight muscle degeneration and mitochondrial morphological alterations that result from mutations in PINK1 and parkin are strongly suppressed by increased drp1 gene dosage and by heterozygous loss-of-function mutations affecting the mitochondrial fusion-promoting factors OPA1 and Mfn2. Finally, we find that an eye phenotype associated with increased PINK1/Parkin pathway activity is suppressed by perturbations that reduce mitochondrial fission and enhanced by perturbations that reduce mitochondrial fusion. Our studies suggest that the PINK1/Parkin pathway promotes mitochondrial fission and that the loss of mitochondrial and tissue integrity in PINK1 and parkin mutants derives from reduced mitochondrial fission.
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PMID:The PINK1/Parkin pathway regulates mitochondrial morphology. 1823 Jul 23

In synucleinopathies, including Parkinson's disease, partially ubiquitylated alpha-synuclein species phosphorylated on serine 129 (P(S129)-alpha-synuclein) accumulate abnormally. Parkin, an ubiquitin-protein ligase that is dysfunctional in autosomal recessive parkinsonism, protects against alpha-synuclein-mediated toxicity in various models.We analyzed the effects of Parkin deficiency in a mouse model of synucleinopathy to explore the possibility that Parkin and alpha-synuclein act in the same biochemical pathway. Whether or not Parkin was present, these mice developed an age-dependent neurodegenerative disorder preceded by a progressive decline in performance in tasks predictive of sensorimotor dysfunction. The symptoms were accompanied by the deposition of P(S129)-alpha-synuclein but not P(S87)-alpha-synuclein in neuronal cell bodies and neuritic processes throughout the brainstem and the spinal cord; activation of caspase 9 was observed in 5% of the P(S129)-alpha-synuclein-positive neurons. As in Lewy bodies, ubiquitin-immunoreactivity, albeit less abundant, was invariably co-localized with P(S129)-alpha-synuclein. During late disease stages, the disease-specific neuropathological features revealed by ubiquitin- and P(S129)-alpha-synuclein-specific antibodies were similar in mice with or without Parkin. However, the proportion of P(S129)-alpha-synuclein-immunoreactive neuronal cell bodies and neurites co-stained for ubiquitin was lower in the absence than in the presence of Parkin, suggesting less advanced synucleinopathy. Moreover, sensorimotor impairment and manifestation of the neurodegenerative phenotype due to overproduction of human alpha-synuclein were significantly delayed in Parkin-deficient mice.These findings raise the possibility that effective compensatory mechanisms modulate the phenotypic expression of disease in parkin-related parkinsonism.
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PMID:Parkin deficiency delays motor decline and disease manifestation in a mouse model of synucleinopathy. 1968 May 61

Mutations in PTEN-induced putative kinase 1 (PINK1) or parkin cause autosomal recessive forms of Parkinson disease (PD), but how these mutations trigger neurodegeneration is poorly understood and the exact functional relationship between PINK1 and parkin remains unclear. Here, we report that PINK1 regulates the E3 ubiquitin-protein ligase function of parkin through direct phosphorylation. We find that phosphorylation of parkin by PINK1 activates parkin E3 ligase function for catalyzing K63-linked polyubiquitination and enhances parkin-mediated ubiquitin signaling through the IkappaB kinase/nuclear factor kappaB (NF-kappaB) pathway. Furthermore, the ability of PINK1 to promote parkin phosphorylation and activate parkin-mediated ubiquitin signaling is impaired by PD-linked pathogenic PINK1 mutations. Our findings support a direct link between PINK1-mediated phosphorylation and parkin-mediated ubiquitin signaling and implicate the deregulation of the PINK1/parkin/NF-kappaB neuroprotective signaling pathway in the pathogenesis of PD.
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PMID:Phosphorylation of parkin by Parkinson disease-linked kinase PINK1 activates parkin E3 ligase function and NF-kappaB signaling. 1988 Apr 20


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