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Parkin- an E3 Ubiquitin Ligase with Multiple Substrates

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Parkin- an E3 Ubiquitin Ligase with Multiple Substrates rs Disea me se ei & h P z l a Sandebring and Cedazo-Mínguez A. J Alzheimers Dis Parkinsonism 2012, S10 A r k f Journal of i n o s l o a DOI: 10.4172/2161-0460.S10-002 n n r i s u m o J ISSN: 2161-0460 Alzheimer’s Disease & Parkinsonism Review Article Open Access Parkin- An E3 Ubiquitin Ligase with Multiple Substrates Anna Sandebring* and Angel Cedazo-Mínguez Karolinska Institutet Department of NVS, KI-Alzheimer’s Disease Research Center, NOVUM floor 5, 141 57 Huddinge, Sweden Abstract Parkinson’s disease is a common neurodegenerative disorder. The clinical symptoms arise from a substantial loss of dopaminergic neurons in substantia nigra pars compacta, which causes motor symptoms such as bradykinesia and tremor. Although the majority of PD cases are sporadic, there is a growing number of genes shown to be involved in causing parkinsonism that manifests with similar pathology to the idiopathic disease. The most common cause to autosomal recessive parkinson’s disease (ARPD) is mutations in the gene encoding for parkin- an E3 ubiquitin ligase with widespread functions in the cell. In this review we summarize the substrates identified for parkin and which functions these imply in the cell. Elucidating the mechanism of functions of these substrates may contribute with clues on which pathways to study further in Parkinson’s disease pathology. Abbreviations: ARPD: Autosomal Recessive Parkinson Disease; implies that the unfolded protein response is involved in the pathogenic CDC-rel: Cell Division Control related protein; Drp1: Dynamin process ultimately leading to neuronal death [4]. related protein 1; EGFR: Epidermal Growth Factor Receptor; FBP1: The complex machinery of protein ubiquitylation engages the Far upstream binding element; HDAC4: Histone Deacetylase 4; Hsp70: activity of ligases; The E1 ligases are required to activate the small Heat shock protein 70; IBR: in between RING; Iκκγ: Inhibitor of kappa ubiquitin monomers in an ATP demanding process, followed by E2 B Kinase; KO: Knock-Out; LB: Lewy Body; Miro: Mitochondrial Rho; ligase conjugation to ubiquitin, which then works in conjunction with NF-κB: Nuclear Factor κB; Pael-R: Parkin associated endothelial the E3 ligase to transfer ubiquitin to the E3 ligase bound substrate. The receptor; PD: Parkinson Disease; PDCD2-1: Programmed cell death E3 ligase thereby facilitates the isopeptide bond between the substrate 2 isoform-1; PICK1: Protein Interacting with C-kinase 1; PLC: and ubiquitin. There are multiple shapes of ubiquitin chains, arising Phospholipase C; RanBP2: Ran Binding Protein 2; RING: Really from the linkage between crucial lysine residues within the ubiqutin Interesting New Gene; SNpc: Substantia Nigra pars compacta; TRAF2: monomer. The complexity in protein ubiquitylation is thereby due TNF-receptor Associated Factor 2; UBL: Ubiquitin-like; VDAC: to the ability of ubiqutin to generate a variety of different polymer Voltage Dependent Anion Channel conformations, having varying consequences for the target substrates. Parkinson’s Disease Ubiquitylation can lead to proteasomal degradation, but depending on the mediating ligases and the structure of the formed ubiquitin Parkinson’s disease (PD) is the most common neurodegenerative chain, targeted proteins can also undergo endocytosis and lysosomal motor disorder and is clinically diagnosed by bradykinesia, degradation, or translocate and participate in cellular signaling (for rigidity, resting tremor and postural instability. The disease is reviews on ubiquitylation, see [5,6]). The ubiquitin pathway has been neuropathologically characterized by substantial loss of dopaminergic implicated in the pathogenesis of several diseases, some of them of neurons in the substantia nigra pars compacta (SNpc) and the presence genetic origin, including neurodegenerative diseases such as PD, of α-synuclein positive inclusions, termed Lewy bodies (LB) (PD ataxia and Alzheimer’s disease (for review on the ubiquitin pathway in reviewed in [1]). neurodegeneration, see [7]). The discovery of genes involved in the development of parkinsonism Parkin is an E3 Ubiquitin Ligase has contributed immensely to the comprehension of disease pathogenesis. Although PD is mainly a sporadic disorder, studies The ARPD associated gene product parkin has E3 ubiqutin ligase during the last decades have identified predisposing genetic risk factors activity and is hence serving as a substrate recognition enzyme within and a direct link to 16 loci and 11 genes. A growing understanding the cell [8]. Parkin has an N-terminal ubiquitin-like (UBL) domain of the genomics behind PD is providing important tools for studying and two RING (really interesting new gene) domains, flanked by a disease related mechanisms. Autosomal Recessive Parkinson’s disease cysteine rich in between RING (IBR) domain near the C-terminus (ARPD) is caused by mutations in parkin, PTEN induced kinase-1 [9]. The RING domain E3 ligase family is the largest group of E3 (PINK1) or DJ-1, where mutations in parkin are the most common (for ligases and is characterized by the binding of two zinc ions in a reviews on genetics behind PD, see [2,3]). histidine and cysteine rich motif of the RING finger domain resulting Parkin is an E3 ubiquitin ligase expressed in several organs, but abundantly in the brain including the SNpc. In this review, we go *Corresponding author: Anna Sandebring, Karolinska Institutet., Department of through the identified parkin substrates and give an overview of which NVS, KI-Alzheimer’s Disease Research Center, NOVUM, 141 57 Huddinge, Swe- den, Tel: +468 58 58 36 67; Fax: +468 58 58 83 80; E-mail: [email protected] cellular functions that are associated to their respective roles, and thereby plausibly involved in PD pathogenesis. Received march 19, 2012; Accepted May 07, 2012; Published May 09, 2012 Citation: Sandebring A, Cedazo-Mínguez A (2012) Parkin- An E3 Ubiquitin Protein Ubiquitylation Ligase with Multiple Substrates. J Alzheimers Dis Parkinsonism S10:002. doi:10.4172/2161-0460.S10-002 Post-translational modification by protein ubiquitylation is the most important proteolytic quality control system in the cell. Copyright: © 2012 Sandebring A, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits Pathological ubiquitin positive inclusion bodies in brain material unrestricted use, distribution, and reproduction in any medium, provided the from patients suffering from PD or other neurodegenerative diseases, original author and source are credited. J Alzheimers Dis Parkinsonism Neurodegenerative Disorders ISSN:2161-0460 JADP an open access journal Citation: Sandebring A, Cedazo- Mínguez A (2012) Parkin- An E3 Ubiquitin Ligase with Multiple Substrates. J Alzheimers Dis Parkinsonism S10:002. doi:10.4172/2161-0460.S10-002 Page 2 of 6 in a globular conformation. The role of RING domains is to recruit member of the PSD95/discs large/ZO-1 (PDZ) protein family, that ubiquitin conjugating enzymes, E2 ligases thereby bind to the E3 regulates trafficking of proteins and mediates the assembly of large ligase RING domain where the ubiqutin is discharged and conjugated protein complexes and PICK1 itself is a presynaptic protein known to to the substrate [10]. Over 100 parkin mutations, including exonic associate with channels and receptors. In line with this function, the rearrangements, point mutations and small deletions or insertions authors show that parkin overexpression abolishes the PICK1 mediated have been identified, which places parkin as the most common cause potentiation of Acid-sensing ion channel subunit 2a, suggesting that of ARPD [11]. parkin mediated mono-ubiquitylation deactivates PICK1. Knock­ down of parkin however enhance the excitatory effect from this Parkin mediated ubiquitylation has been shown to involve the channel, which may imply that ARPD involve excitotoxicity through a conjugation to the E2 ubiquitin carrier proteins UbcH7 and UbcH8, lack of PICK1 regulation. which are typically involved in K48-linked polyubiquitylation in order to promote proteasomal degradation, and to UbcH13, which mediate Ubiquitylation and subsequent regulation of the levels of non-degrading K63-linked polyubiquitylation [12-14]. Indeed, several polyglutamine proteins ataxin-2 and -3 has been associated to parkin of the identified parkin substrates do not accumulate in parkin knock­ E3 ligase activity [28,29]. Parkin protects from ataxin-2 mediated out (KO) mice, ARPD parkin or idiopathic PD human brain, supporting neurotoxicity and is involved also in the regulation of the normal protein the notion that parkin is able to mediate different types of ubiquitylation levels [28,29]. When polyglutamine repeats are mutated and expanded, [15-17]. Furthermore, parkin has auto– polyubiquitylating properties, Purkinje neurons degenerate resulting in spinocerebellar ataxia type allowing the protein itself to be degraded by the proteasome [18], as 2. As in PD, neurodegeneration resulting from polyglutamine repeats well as auto– monoubiquitylation and –multiple monoubiquitylating also involves the formation of protein inclusion. Thus, it is possible that activities in vitro [19,20]. Some of the identified mutations in the parkin participates in the clearance of misfolded proteins not only in gene encoding for parkin, have been shown to impair its E3 ubiquitin the PD affected regions, but also for other neurodegenerative diseases. ligase activity for several substrates [12,14,18]. In the sections below, we describe
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