Parkin, Recombinant Protein

PARK2; AR-JP; PDJ; PRKN; LPRS2

For Research Use Only. Not for use in diagnostic procedures.

Chromosome: 6; NC_000006.11 (161768590..163148834, complement). Location: 6q25.2-q27

Sf9 insect cells

50mM Tris-HCl, pH 7.5, 50mM NaCl, 10mM glutathione, 0.1mM EDTA, 0.25mM DTT, 0.1mM PMSF, 25% glycerol.

Store product at -70 degree C. For optimal storage, aliquot target into smaller quantities after centrifugation and store at recommended temperature. For most favorable performance, avoid repeated handling and multiple freeze/thaw cycles.

Small volumes of PARK2 recombinant protein vial(s) may occasionally become entrapped in the seal of the product vial during shipment and storage. If necessary, briefly centrifuge the vial on a tabletop centrifuge to dislodge any liquid in the container`s cap. Certain products may require to ship with dry ice and additional dry ice fee may apply.

Recombinant full-length human Parkin was expressed by baculovirus in Sf9 insect cells using an N-terminal GST tag.

Scientific Background: Parkin or parkinson protein 2 is a RING domain-containing E3 ubiquitin protein ligase involved in proteasome-dependent degradation of proteins. Mutations in Parkin can lead to Prakinson's disease. Parkin is important for mitochondrial quality control by lysosome-dependent degradation of damaged mitochondria through autophagy, or mitophagy (1). Parkin plays an important role in directly supporting mitochondrial function and protecting mitochondrial genomic integrity from oxidative stress (2). Parkin also has essential role in regulating normal respiratory function in mitochondria and in the protection of cells from oxidative stress.

Ubiquitin Proteins; Signaling Proteins - Ubiquitin Proteins

Western Blot (WB)

~68 kDa[Similar Products]

parkinson protein 2, E3 ubiquitin protein ligase (parkin)

E3 ubiquitin-protein ligase parkin; parkinson juvenile disease protein 2; Parkinson disease (autosomal recessive, juvenile) 2, parkin

E3 ubiquitin-protein ligase parkin

PRKN; Parkinson disease protein 2  [Similar Products]

PRKN2_HUMAN

The precise function of this gene is unknown; however, the encoded protein is a component of a multiprotein E3 ubiquitin ligase complex that mediates the targeting of substrate proteins for proteasomal degradation. Mutations in this gene are known to cause Parkinson disease and autosomal recessive juvenile Parkinson disease. Alternative splicing of this gene produces multiple transcript variants encoding distinct isoforms. Additional splice variants of this gene have been described but currently lack transcript support. [provided by RefSeq, Jul 2008]

Function: Functions within a multiprotein E3 ubiquitin ligase complex, catalyzing the covalent attachment of ubiquitin moieties onto substrate proteins, such as BCL2, SYT11, CCNE1, GPR37, STUB1, a 22 kDa O-linked glycosylated isoform of SNCAIP, SEPT5, ZNF746 and AIMP2. Mediates monoubiquitination as well as 'Lys-48'-linked and 'Lys-63'-linked polyubiquitination of substrates depending on the context. Participates in the removal and/or detoxification of abnormally folded or damaged protein by mediating 'Lys-63'-linked polyubiquitination of misfolded proteins such as PARK7: 'Lys-63'-linked polyubiquitinated misfolded proteins are then recognized by HDAC6, leading to their recruitment to aggresomes, followed by degradation. Mediates 'Lys-63'-linked polyubiquitination of SNCAIP, possibly playing a role in Lewy-body formation. Mediates monoubiquitination of BCL2, thereby acting as a positive regulator of autophagy. Promotes the autophagic degradation of dysfunctional depolarized mitochondria. Mediates 'Lys-48'-linked polyubiquitination of ZNF746, followed by degradation of ZNF746 by the proteasome; possibly playing a role in role in regulation of neuron death. Limits the production of reactive oxygen species (ROS). Loss of this ubiquitin ligase activity appears to be the mechanism underlying pathogenesis of PARK2. May protect neurons against alpha synuclein toxicity, proteasomal dysfunction, GPR37 accumulation, and kainate-induced excitotoxicity. May play a role in controlling neurotransmitter trafficking at the presynaptic terminal and in calcium-dependent exocytosis. Regulates cyclin-E during neuronal apoptosis. May represent a tumor suppressor gene. Ref.10 Ref.11 Ref.20 Ref.22 Ref.24 Ref.26 Ref.27 Ref.31 Ref.32 Ref.33 Ref.35 Ref.36 Ref.37 Ref.38

Pathway: Protein modification; protein ubiquitination.

Subunit structure: Forms an E3 ubiquitin ligase complex with UBE2L3 or UBE2L6. Mediates 'Lys-63'-linked polyubiquitination by associating with UBE2V1. Part of a SCF-like complex, consisting of PARK2, CUL1 and FBXW7. Interacts with SNCAIP. Binds to the C2A and C2B domains of SYT11. Interacts and regulates the turnover of SEPT5. Part of a complex, including STUB1, HSP70 and GPR37. The amount of STUB1 in the complex increases during ER stress. STUB1 promotes the dissociation of HSP70 from PARK2 and GPR37, thus facilitating PARK2-mediated GPR37 ubiquitination. HSP70 transiently associates with unfolded GPR37 and inhibits the E3 activity of PARK2, whereas, STUB1 enhances the E3 activity of PARK2 through promotion of dissociation of HSP70 from PARK2-GPR37 complexes. Interacts with PSMD4 and PACRG. Interacts with LRRK2. Interacts with RANBP2. Interacts with SUMO1 but not SUMO2, which promotes nuclear localization and autoubiquitination. Interacts (via first RING-type domain) with AIMP2 (via N-terminus). Interacts with PSMA7 and RNF41. Interacts with PINK1. Ref.12 Ref.14 Ref.17 Ref.18 Ref.19 Ref.20 Ref.25 Ref.26 Ref.27 Ref.28 Ref.29 Ref.30 Ref.33 Ref.34 Ref.35 Ref.36 Ref.37 Ref.38 Ref.39

Subcellular location: Cytoplasm › cytosol. Nucleus. Endoplasmic reticulum. Mitochondrion. Note: Mainly localizes in the cytosol. Colocalizes with SYT11 in neutrites. Colocalizes with SNCAIP in brainstem Lewy bodies. Relocates to dysfunctional mitochondria that have lost the mitochondrial membrane potential; recruitment to mitochondria is PINK1-dependent. Ref.2 Ref.9 Ref.15 Ref.30 Ref.31 Ref.32 Ref.35 Ref.36

Tissue specificity: Highly expressed in the brain including the substantia nigra. Expressed in heart, testis and skeletal muscle. Expression is down-regulated or absent in tumor biopsies, and absent in the brain of PARK2 patients. Overexpression protects dopamine neurons from kainate-mediated apoptosis. Found in serum (at protein level). Ref.2

Domain: The ubiquitin-like domain binds the PSMD4 subunit of 26S proteasomes. Ref.16

Post-translational modification: Auto-ubiquitinates in an E2-dependent manner leading to its own degradation. Also polyubiquitinated by RNF41 for proteasomal degradation.S-nitrosylated. The inhibition of PARK2 ubiquitin E3 ligase activity by S-nitrosylation could contribute to the degenerative process in PD by impairing the ubiquitination of PARK2 substrates.

Involvement in disease: Parkinson disease (PARK) [MIM:168600]: A complex neurodegenerative disorder characterized by bradykinesia, resting tremor, muscular rigidity and postural instability. Additional features are characteristic postural abnormalities, dysautonomia, dystonic cramps, and dementia. The pathology of Parkinson disease involves the loss of dopaminergic neurons in the substantia nigra and the presence of Lewy bodies (intraneuronal accumulations of aggregated proteins), in surviving neurons in various areas of the brain. The disease is progressive and usually manifests after the age of 50 years, although early-onset cases (before 50 years) are known. The majority of the cases are sporadic suggesting a multifactorial etiology based on environmental and genetic factors. However, some patients present with a positive family history for the disease. Familial forms of the disease usually begin at earlier ages and are associated with atypical clinical features.Note: Disease susceptibility may be associated with variations affecting the gene represented in this entry. Heterozygous mutations act as susceptibility alleles for late-onset Parkinson disease (Ref.59 and Ref.60). Ref.1 Ref.11 Ref.14 Ref.15 Ref.18 Ref.35 Ref.36 Ref.37 Ref.40 Ref.42 Ref.44 Ref.46 Ref.48 Ref.49 Ref.50 Ref.51 Ref.52 Ref.54 Ref.55 Ref.56 Ref.57 Ref.58 Ref.59 Ref.60 Ref.62Parkinson disease 2 (PARK2) [MIM:600116]: A neurodegenerative disorder characterized by bradykinesia, rigidity, postural instability, tremor, and onset usually before 40. It differs from classic Parkinson disease by early DOPA-induced dyskinesia, diurnal fluctuation of the symptoms, sleep benefit, dystonia and hyper-reflexia. Dementia is absent. Pathologically, patients show loss of dopaminergic neurons in the substantia nigra, similar to that seen in Parkinson disease; however, Lewy bodies (intraneuronal accumulations of aggregated proteins) are absent.Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.1 Ref.11 Ref.14 Ref.15 Ref.35 Ref.37 Ref.40 Ref.42 Ref.44 Ref.46 Ref.48 Ref.49 Ref.50 Ref.51 Ref.52 Ref.54 Ref.55 Ref.56 Ref.57 Ref.58 Ref.59 Ref.60 Ref.62Defects in PARK2 may be involved in the development and/or progression of ovarian cancer.

Miscellaneous: The parkin locus (PRKN), adjacent to the 6q telomere is hyper-recombinable and lies within FRA6E, the third most common fragile site in tumor tissue.Members of the RBR family are atypical E3 ligases. They interact with the E2 conjugating enzyme UBE2L3 and function like HECT-type E3 enzymes: they bind E2s via the first RING domain, but require an obligate trans-thiolation step during the ubiquitin transfer, requiring a conserved cysteine residue in the second RING domain (Ref.38).

Sequence similarities: Belongs to the RBR family. Parkin subfamily.Contains 1 IBR-type zinc finger.Contains 2 RING-type zinc fingers.Contains 1 ubiquitin-like domain.

1. Yoshii, S. R. et.al: Parkin mediates proteasome-dependent protein degradation and rupture of the outer mitochondrial membrane. J. Biol. Chem. 286: 19630-19640, 2011.
2. Rothfuss, O. et.al: Parkin promotes mitochondrial genome integrity and supports mitochondrial DNA repair. Hum. Molec. Genet. 18: 3832-3850, 2009.

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