Ubiquitin immunoreactivity of multiple polypeptides in rat brain synaptic membranes

Chapman, Andrew. P.; Courtney, Sheila C.; Smith, Stuart; Rider, Christopher C.; Beesley, Philip

doi:10.1042/bst020155s

Cited by 16 publications

(12 citation statements)

References 3 publications

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“…Whether CDCrel-1 regulates dopamine release awaits further clarification, but failure of CDCrel-1 to be degraded by familial-linked Parkin mutations could increase the steady-state level of CDCrel-1 and thus potentially inhibit dopamine release and contribute to a Parkinsonian state. The mechanism underlying the degradation and turnover of synaptic vesicle-associated proteins has not been clarified, despite the identification of ubiquitin in the postsynaptic density and synaptic terminals (38)(39)(40). However, it is likely that Parkin or other nervous system-enriched E3s may play a prominent role in regulation of synaptic vesicle-associated protein levels.…”

Section: Discussionmentioning

confidence: 99%

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

Zhang

Gao

Chung

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

907

744

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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...

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Section: Discussionmentioning

confidence: 99%

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

Zhang

Gao

Chung

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

907

744

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“…2 The ubiquitin-proteasome pathway plays a crucial role in the degradation of proteins involved in a variety of cellular processes, including differentiation, proliferation, and apoptosis (65,71,76). However, the role of the ubiquitin-proteasome pathway in the degradation of synaptic vesicle-associated proteins remains poorly characterized, despite the identification of ubiquitin in synaptic terminals (77,78). In this study, we have shown that synaptophysin, an integral membrane protein of synaptic vesicles, is ubiquitinated and degraded by the proteasome pathway.…”

Section: Siah Associates With the E2 Ubiquitin-conjugating Enzyme Ubcmentioning

confidence: 99%

Regulation of Synaptophysin Degradation by Mammalian Homologues of Seven in Absentia

Wheeler

Chin

et al. 2002

Journal of Biological Chemistry

148

134

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Synaptophysin is an integral membrane protein of synaptic vesicles characterized by four transmembrane domains with both termini facing the cytoplasm. Although synaptophysin has been implicated in neurotransmitter release, and decreased synaptophysin levels have been associated with several neurodegenerative diseases, the molecular mechanism that regulates the degradation of synaptophysin remains unsolved. Using the cytoplasmic C terminus of synaptophysin as bait in a yeast two-hybrid screen, we identified two synaptophysin-binding proteins, Siah-1A and Siah-2, which are rat homologues of Drosophila Seven in Absentia. We demonstrated that Siah-1A and Siah-2 associate with synaptophysin both in vitro and in vivo and defined the binding domains of synaptophysin and Siah that mediate their association. Siah proteins exist in both cytosolic and membrane-associated pools and co-localize with synaptophysin on synaptic vesicles and early endosomes. In addition, Siah proteins interact specifically with the brain-enriched E2 ubiquitin-conjugating enzyme UbcH8 and facilitate the ubiquitination of synaptophysin. Furthermore, overexpression of Siah proteins promotes the degradation of synaptophysin via the ubiquitin-proteasome pathway. Our findings indicate that Siah proteins function as E3 ubiquitin-protein ligases to regulate the ubiquitination and degradation of synaptophysin.

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“…The ubiquitin-proteasome pathway plays a crucial role in the degradation of proteins involved in a variety of cellular processes, including differentiation, proliferation, and apoptosis. However, the role of the ubiquitin-proteasome pathway in the degradation of presynaptic proteins remains poorly characterized, despite the presence of ubiquitin at nerve terminals (3)(4)(5). In the ubiquitin-proteasome pathway, substrates are marked for degradation by covalent linkage to ubiquitin.…”

mentioning

confidence: 99%

Staring, a Novel E3 Ubiquitin-Protein Ligase That Targets Syntaxin 1 for Degradation

Chin

Vavalle

Lian

2002

Journal of Biological Chemistry

110

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Syntaxin 1 is an essential component of the neurotransmitter release machinery, and regulation of syntaxin 1 expression levels is thought to contribute to the mechanism underlying learning and memory. However, the molecular events that control the degradation of syntaxin 1 remain undefined. Here we report the identification and characterization of a novel RING finger protein, Staring, that interacts with syntaxin 1. Staring is expressed throughout the brain, where it exists in both cytosolic and membrane-associated pools. Staring binds and recruits the brain-enriched E2 ubiquitin-conjugating enzyme UbcH8 to syntaxin 1 and facilitates the ubiquitination and proteasome-dependent degradation of syntaxin 1. These findings suggest that Staring is a novel E3 ubiquitin-protein ligase that targets syntaxin 1 for degradation by the ubiquitin-proteasome pathway.Modulation of protein degradation is a major mechanism by which cells regulate the expression levels of specific proteins and consequently the cellular processes that these proteins participate in (1, 2). The ubiquitin-proteasome pathway plays a crucial role in the degradation of proteins involved in a variety of cellular processes, including differentiation, proliferation, and apoptosis. However, the role of the ubiquitin-proteasome pathway in the degradation of presynaptic proteins remains poorly characterized, despite the presence of ubiquitin at nerve terminals (3-5). In the ubiquitin-proteasome pathway, substrates are marked for degradation by covalent linkage to ubiquitin. The ubiquitinated substrate proteins are then recognized and degraded by the 26 S proteasome (1, 2, 6). Ubiquitination involves a highly specific enzyme cascade in which ubiquitin is first activated by an E1 1 ubiquitin-activating enzyme and then transferred to an E2 ubiquitin-conjugating enzyme and finally ligated to the substrate by an E3 ubiquitin-protein ligase (1,7,8). The E3 ubiquitin-protein ligase plays an essential role in determining the specificity of ubiquitination and subsequent protein degradation. Consistent with this role, it is estimated that an organism such as a human contains over 100 E3 ubiquitin ligases, in contrast to a single E1 ubiquitin-activating enzyme and about a dozen E2 ubiquitin-conjugating enzymes (9). Despite the importance of E3 ubiquitin-protein ligases in specific protein degradation and the estimated presence of more than 100 E3 ligases in the human genome, only a few E3 ligases have been characterized at the molecular level.Syntaxin 1 is a neuronal membrane protein that was originally identified as a binding partner for synaptotagmin and the N-type calcium channel (10 -12). It is well established that syntaxin 1 functions as a synaptic t-SNARE to mediate synaptic vesicle exocytosis at nerve terminals (13)(14)(15). Syntaxin 1 appears early during embryonic development (16, 17), and its expression level is dramatically up-regulated during synapse formation and brain maturation (16 -19). Regulation of syntaxin 1 levels may contribute to the mechanism unde...

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Ubiquitin immunoreactivity of multiple polypeptides in rat brain synaptic membranes

Cited by 16 publications

References 3 publications

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

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

Regulation of Synaptophysin Degradation by Mammalian Homologues of Seven in Absentia

Staring, a Novel E3 Ubiquitin-Protein Ligase That Targets Syntaxin 1 for Degradation

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