Parkin- An E3 Ubiquitin Ligase with Multiple Substrates

Sandebring, Anna

doi:10.4172/2161-0460.s10-002

Cited by 13 publications

(18 citation statements)

References 68 publications

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“…Many reports indicate that parkin phosphorylation modulates its ubiquitin E3 ligase activity, consequently leading to the modulation of either steady‐state levels or functional activities of its target proteins, such as TRAF2, IKKγ, Synphilin‐1, p38, and Drp1 (Sandebring and Cedazo‐Minguez ). Thus, we investigated the effect of Dyrk1A‐mediated phosphorylation on parkin activity.…”

Section: Resultsmentioning

confidence: 99%

“…Immunoblot analysis of cell lysates with p53 antibody was performed to test the effect of roscovitine treatment as a positive control. modulation of either steady-state levels or functional activities of its target proteins, such as TRAF2, IKKc, Synphilin-1, p38, and Drp1 (Sandebring and Cedazo-Minguez 2012). Thus, we investigated the effect of Dyrk1A-mediated phosphorylation on parkin activity.…”

Section: Dyrk1a-induced Phosphorylation Does Not Affect Localization mentioning

confidence: 99%

“…). A number of parkin substrates are reported, including RanBP, PaelR, synphilin‐1, p38 subunit of aminoacyl‐tRNA synthetase complex, IκB kinase γ, and Tumor necrosis factor (TNF) Receptor‐associated Factor 2 (TRAF2) (Sandebring and Cedazo‐Minguez ).…”

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confidence: 99%

“…Like many other ubiquitin ligases with a RING domain, parkin is also activated by E2 dependent auto-ubiquitination via mono-ubiquitin or poly-ubiquitin chains (Hampe et al 2006;Joch et al 2007). A number of parkin substrates are reported, including RanBP, PaelR, synphilin-1, p38 subunit of aminoacyl-tRNA synthetase complex, IjB kinase c, and Tumor necrosis factor (TNF) Receptor-associated Factor 2 (TRAF2) (Sandebring and Cedazo-Minguez 2012).…”

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Dyrk1A phosphorylates parkin at Ser‐131 and negatively regulates its ubiquitin E3 ligase activity

Chung

2015

Journal of Neurochemistry

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Mutations of parkin are associated with the occurrence of autosomal recessive familial Parkinson's disease (PD). Parkin acts an E3 ubiquitin ligase, which ubiquitinates target proteins and subsequently regulates either their steady-state levels through the ubiquitin-proteasome system or biochemical properties. In this study, we identify a novel regulatory mechanism of parkin by searching for new regulatory factors. After screening human fetal brain using a yeast two hybrid assay, we found dual-specificity tyrosine-(Y)-phosphorylationregulated kinase 1A (Dyrk1A) as a novel binding partner of parkin. We also observed that parkin interacts and co-localizes with Dyrk1A in mammalian cells. In addition, Dyrk1A directly phosphorylated parkin at Ser-131, causing the inhibition of its E3 ubiquitin ligase activity. Moreover, Dyrk1A-mediated phosphorylation reduced the binding affinity of parkin to its ubiquitin-conjugating E2 enzyme and substrate, which could be the underlying inhibitory mechanism of parkin activity. Furthermore, Dyrk1A-mediated phosphorylation inhibited the neuroprotective action of parkin against 6-hydroxydopamine toxicity in dopaminergic SH-SY5Y cells. These findings suggest that Dyrk1A acts as a novel functional modulator of parkin. Parkin phosphorylation by Dyrk1A suppresses its E3 ubiquitin ligase activity potentially contributing to the pathogenesis of PD under PD-inducing pathological conditions.

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Section: Resultsmentioning

confidence: 99%

Section: Dyrk1a-induced Phosphorylation Does Not Affect Localization mentioning

confidence: 99%

mentioning

confidence: 99%

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confidence: 99%

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Dyrk1A phosphorylates parkin at Ser‐131 and negatively regulates its ubiquitin E3 ligase activity

Chung

2015

Journal of Neurochemistry

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“…Moreover, Parkin has been shown to catalyze the formation of various ubiquitin modifications ranging from (multi-) monoubiquitin to poly-ubiquitin chains with distinct characteristics (Sandebring and Cedazo-Mínguez, 2012). Ubiquitin itself contains seven internal lysine residues that all can be used to generate ubiquitin chains of unique topologies and biological functions (Komander and Rape, 2012).…”

Section: Introductionmentioning

confidence: 99%

Select E2 enzymes differentially regulate parkin activation and mitophagy

Fiesel

Moussaud-Lamodière

Ando

et al. 2014

Journal of Cell Science

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Loss-of-function mutations in the genes encoding PINK1 and Parkin (also known as PARK2) are the most common causes of recessive Parkinson's disease. Both together mediate the selective degradation of mitochondrial proteins and whole organelles via the proteasome and the autophagy-lysosome pathway (mitophagy). The mitochondrial kinase PINK1 activates and recruits the E3 ubiquitin ligase Parkin to de-energized mitochondria. However, the cognate E2 co-enzymes of Parkin in this ubiquitin-dependent pathway have not been investigated. Here, we discovered a total of four E2s that either positively or negatively regulate the activation, translocation and enzymatic functions of Parkin during mitochondrial quality control. UBE2D family members and UBE2L3 redundantly charged the RING-HECT hybrid ligase Parkin with ubiquitin, resulting in its initial activation and translocation to mitochondria. UBE2N, however, primarily operated through a different mechanism in order to mediate the proper clustering of mitochondria, a prerequisite for degradation. Strikingly, in contrast to UBE2D, UBE2L3 and UBE2N, depletion of UBE2R1 resulted in enhanced Parkin translocation and clustering upon mitochondrial uncoupling. Our study uncovered redundant, cooperative or antagonistic functions of distinct E2 enzymes in the regulation of Parkin and mitophagy that might suggest a putative role in Parkinson's disease pathogenesis.

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Lipid profiling of parkin‐mutant human skin fibroblasts

Lobasso

Tanzarella

Vergara

et al. 2017

Journal Cellular Physiology

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Parkin mutations are a major cause of early-onset Parkinson's disease (PD). The impairment of protein quality control system together with defects in mitochondria and autophagy process are consequences of the lack of parkin, which leads to neurodegeneration. Little is known about the role of lipids in these alterations of cell functions. In the present study, parkin-mutant human skin primary fibroblasts have been considered as cellular model of PD to investigate on possible lipid alterations associated with the lack of parkin protein. Dermal fibroblasts were obtained from two unrelated PD patients with different parkin mutations and their lipid compositions were compared with that of two control fibroblasts. The lipid extracts of fibroblasts have been analyzed by combined matrix-assisted laser desorption/ionization-time-of-flight mass spectrometry (MALDI-TOF/MS) and thin-layer chromatography (TLC). In parallel, we have performed direct MALDI-TOF/MS lipid analyses of intact fibroblasts by skipping lipid extraction steps. Results show that the proportions of some phospholipids and glycosphingolipids were altered in the lipid profiles of parkin-mutant fibroblasts. The detected higher level of gangliosides, phosphatidylinositol, and phosphatidylserine could be linked to dysfunction of autophagy and mitochondrial turnover; in addition, the lysophosphatidylcholine increase could represent the marker of neuroinflammatory state, a well-known component of PD.

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Parkin- An E3 Ubiquitin Ligase with Multiple Substrates

Cited by 13 publications

References 68 publications

Dyrk1A phosphorylates parkin at Ser‐131 and negatively regulates its ubiquitin E3 ligase activity

Dyrk1A phosphorylates parkin at Ser‐131 and negatively regulates its ubiquitin E3 ligase activity

Select E2 enzymes differentially regulate parkin activation and mitophagy

Lipid profiling of parkin‐mutant human skin fibroblasts

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