Parkin functions as an E2-dependent ubiquitin– protein ligase and promotes the degradation of the synaptic vesicle-associated protein, CDCrel-1

Abstract

P arkinson's disease (PD) is the second most prevalent neurodegenerative disorder, but the etiology remains poorly understood (1, 2). Patients with PD suffer from rigidity, slowness of movement, tremor, and disturbances of balance (1, 2). PD is characterized by the progressive loss of dopamine-containing neurons in the substantia nigra pars compacta (3, 4) and the accumulation of Lewy bodies, proteinaceous intracytoplasmic accumulations of eosinophilic material that stain for ubiquitin (5). Novel insights into the molecular mechanisms of the pathogenesis of PD have come from the identification of genes associated with rare forms of familial PD (6). Mutations in ␣-synuclein (A53T and A30P) are linked to autosomal dominant PD (7,8). This led to the discovery that ␣-synuclein is a major component of Lewy bodies and suggests that derangements in ␣-synuclein could be a major cause or contributor to the pathogenesis of sporadic PD (9, 10). Consistent with this notion are observations that overexpression of ␣-synuclein in transgenic fruit flies and mice causes a Parkinsonian phenotype and replicates many of the pathological features of PD (11-13).Other autosomal dominant genes or loci linked to PD have been described and include a mutation (I93M) in ubiquitin carboxyl-terminal-hydrolase-L1 (14), a member of the ubiquitin C-terminal hydrolase family that hydrolyzes small C-terminal adducts of ubiquitin to generate ubiquitin monomers and is involved in facilitating the degradation and processing of proteins through the 26 S proteasome. Thus, derangements in ubiquitin processing may be linked to the pathogenesis of PD. Linkages to chromosome 2P and 4P have been described, as well as yet to be identified loci, but the genes await identification (15-17).Mutations in the Parkin gene are responsible for autosomal recessive PD (18). Several Parkin-associated pedigrees have been described with both deletions and point mutations, as well as compound heterozygosity causing autosomal recessive PD (19)(20)(21). Recent studies suggest that mutations in Parkin are the major cause of autosomal recessive familial PD (19); thus, understanding the function of Parkin and how mutations interfere with the function of Parkin may provide novel insights into the pathogenesis of PD. The function of the Parkin protein remains unknown. However, Parkin shows mild homology to ubiquitin at the N terminus and contains two ring-finger motifs and an in-between ring-finger (IBR) domain at the C terminus (22). Recently, a few proteins with ring-finger motifs similar to Parkin were shown to be involved in E2-dependent ubiquitination (23-26). Ubiquitination requires the ATP-dependent activation of ubiquitin by the ubiquitin-activating enzyme E1. Ubiquitin is transferred to an E2 ubiquitin-conjugating enzyme, which works in conjunction with an E3 ubiquitin-protein ligase to ubiquitinate substrate proteins (23,24). The existence of two ring-finger motifs and the N-terminal homology to ubiquitin suggests that Parkin may be involved in the ubiquitination pathw...

Attenuation of proteolysis‐mediated cyclin E regulation by alternatively spliced Parkin in human colorectal cancers

“…[1][2][3] Parkin is developmentally regulated with induced expression during cell differentiation, and little to no expression in immature cells. 4 Several putative candidate substrates of Parkin-mediated proteolysis have been identified, including a-synphilin, a-synuclein interacting protein, synphilin-1 and Pael-R. 5,6 Recently, it was revealed that deficiency of Parkin potentiates the accumulation of cyclin E protein in cultured postmitotic neurons exposed to the glutamatergic excitotoxin kainate, suggesting that the cell cycle regulator, cyclin E, is a putative substrate of the Parkin ubiquitin ligase complex in neurons.…”

Parkin-mediated Monoubiquitination of the PDZ Protein PICK1 Regulates the Activity of Acid-sensing Ion Channels

“…In contrast, neither CASK nor PICK1 binds to a GST-IR construct containing the familial PD-linked mutation, W453stop (GST-IR W453* ). This mutation is particularly interesting because it truncates only the last 13 amino acids of parkin, eliminating its PDZ-binding motif, but leaves the critical E2-binding RING domain intact (Lucking et al, 2000;Zhang et al, 2000). Interestingly, although CASK contains a wellcharacterized class II PDZ domain, the PDZ domain of PICK1 can interact with both type I and type II as well as with atypical PDZ ligands (Staudinger et al, 1997;Dev et al, 1999;Williams et al, 2003;Madsen et al, 2005).…”

“…The ensuing accumulation of parkin substrates is believed, in turn, to induce the cellular toxicity and dopamine neuron loss seen in PD. Although numerous parkin substrates have been identified (Zhang et al, 2000;Chung et al, 2001;Imai et al, 2001;Corti et al, 2003;Staropoli et al, 2003), there is still controversy as to which of these accumulate in the brains of parkin knockout (KO) mice (Goldberg et al, 2003;Itier et al, 2003;Von Coelln et al, 2004;Ko et al, 2005;Perez and Palmiter, 2005;Periquet et al, 2005) and as to their respective roles in the pathogenesis of PD (Cookson, 2005;Moore et al, 2005).…”

“…The ensuing accumulation of parkin substrates is believed, in turn, to induce the cellular toxicity and dopamine neuron loss seen in PD. Although numerous parkin substrates have been identified (Zhang et al, 2000;Chung et al, 2001;Imai et al, 2001;Corti et al, 2003;Staropoli et al, 2003), there is still controversy as to which of these accumulate in the brains of parkin knockout (KO) mice (Goldberg et al, 2003;Itier et al, 2003;Von Coelln et al, 2004;Ko et al, 2005;Perez and Palmiter, 2005;Periquet et al, 2005) and as to their respective roles in the pathogenesis of PD (Cookson, 2005;Moore et al, 2005).In addition to its traditional role, Ub can serve as a reversible posttranslational modification that regulates the function of tagged proteins without necessarily leading to their destruction by the proteasome (Hicke and Dunn, 2003;Mukhopadhyay and Riezman, 2007). Depending on the length and architecture of the Ub chain, ubiquitination has been implicated in a variety of cellular functions as diverse as signal transduction, transcription, and membrane trafficking (Mukhopadhyay and Riezman, 2007).…”

Progress in the pathogenesis and genetics of Parkinson's disease

“…Since then many parkin-interacting proteins have been reported; the following are substrate candidates: CDCrel-1 (Zhang et al 2000), which is believed to be negatively regulating transmitter release; glycosylated a-synuclein (Shimura et al 2001); synphilin-1 (Chung et al 2001), which is an a-synuclein-interacting protein; PAEL-receptor , which is an endoplasmic reticulum protein; p38 (Corti et al 2003 (Smith et al 2005); and 14-3-3h (Sato et al 2006a,b). In addition, non-lysine 48-related ubiquitylation substrates were reported.…”