Parkin and CASK/LIN-2 Associate via a PDZ-mediated Interaction and Are Co-localized in Lipid Rafts and Postsynaptic Densities in Brain

Fallon, Lara; Croft, Benjamin G.; Labib, Noura; Gu, Wen‐Jie; Fon, Edward A.

doi:10.1074/jbc.m109806200

Cited by 173 publications

(132 citation statements)

References 36 publications

Supporting

Mentioning

129

Contrasting

Order By: Relevance

“…PDZ domain-containing proteins often function in trafficking or as scaffolds for the assembly of large protein complexes. Indeed, we showed that the parkin PDZ-binding motif binds the PDZ protein CASK; however, CASK itself is not ubiquitinated by parkin (Fallon et al, 2002). We reported that parkin colocalizes with CASK in postsynaptic densities (PSD), where many PDZ proteins are localized and that parkin is associated with the NMDA receptor-signaling complex.…”

Section: Introductionmentioning

confidence: 91%

“…We reported previously that the PDZ protein CASK binds to parkin via this C-terminal motif (Fallon et al, 2002). As proteins with PDZ-binding motifs often interact with several distinct PDZ proteins (Srivastava et al, 1998;Dev et al, 1999), we used a candidate approach to identify additional PDZ proteins that interact with the Cterminus of parkin.…”

Section: Parkin Directly Binds the Synaptic Pdz Protein Pick1 Via Itsmentioning

confidence: 99%

“…Next, to test whether parkin affects PICK1 localization in brain, we used a well-established differential centrifugation procedure to prepare synaptic fractions from parkin wild-type and knockout mice (Huttner et al, 1983;Fallon et al, 2002). The procedure yielded crude synaptosomes (P2) and synaptic plasma membrane-(LP1), synaptic vesicle-(LP2), and synaptic cytosol (LS2)-enriched fractions.…”

Section: Molecular Biology Of the Cell 3112mentioning

confidence: 99%

“…Interestingly, many familial PD mutations in parkin are clustered within this E2-binding region (Kitada et al, 1998;Giasson and Lee, 2001), indicating a link between defects in parkin E3 Ub-ligase activity and neurodegeneration. Finally, we have recently shown that the last three amino acids (ϪFDV) at the extreme C-terminus of parkin function as a class II PDZ (PSD-95/discs large/ZO-1) binding motif (Fallon et al, 2002). PDZ domains bind the C-terminal tails of proteins in a sequence-specific manner.…”

mentioning

confidence: 99%

See 3 more Smart Citations

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

Joch

Ase

Chen

et al. 2007

MBoC

Self Cite

128

View full text Add to dashboard Cite

Mutations in the parkin gene result in an autosomal recessive juvenile-onset form of Parkinson's disease. As an E3 ubiquitin-ligase, parkin promotes the attachment of ubiquitin onto specific substrate proteins. Defects in the ubiquitination of parkin substrates are therefore believed to lead to neurodegeneration in Parkinson's disease. Here, we identify the PSD-95/Discs-large/Zona Occludens-1 (PDZ) protein PICK1 as a novel parkin substrate. We find that parkin binds PICK1 via a PDZ-mediated interaction, which predominantly promotes PICK1 monoubiquitination rather than polyubiquitination. Consistent with monoubiquitination and recent work implicating parkin in proteasome-independent pathways, parkin does not promote PICK1 degradation. However, parkin regulates the effects of PICK1 on one of its other PDZ partners, the acid-sensing ion channel (ASIC). Overexpression of wild-type, but not PDZ binding-or E3 ubiquitinligase-defective parkin abolishes the previously described, protein kinase C-induced, PICK1-dependent potentiation of ASIC2a currents in non-neuronal cells. Conversely, the loss of parkin in hippocampal neurons from parkin knockout mice unmasks prominent potentiation of native ASIC currents, which is normally suppressed by endogenous parkin in wild-type neurons. Given that ASIC channels contribute to excitotoxicity, our work provides a mechanism explaining how defects in parkin-mediated PICK1 monoubiquitination could enhance ASIC activity and thereby promote neurodegeneration in Parkinson's disease. INTRODUCTIONParkinson's disease (PD) is characterized by the selective and progressive loss of midbrain dopamine neurons resulting in motor dysfunction and disability. Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism, which accounts for a large proportion of genetically linked PD cases (Kitada et al., 1998). Parkin encodes a 465-amino acid protein (ϳ52 kDa) that is expressed in multiple tissues and functions in the ubiquitin (Ub) system as an E3 Ub-ligase (Shimura et al., 2000). Ubiquitination of substrate proteins is a tightly regulated process, requiring the combined activity of three enzymes: an E1 Ub-activating enzyme, E2 Ub-conjugating enzymes, and E3 Ub-ligases (Hershko and Ciechanover, 1998). E3 Ub-ligases bind substrate proteins and therefore regulate and confer specificity to the ubiquitination reaction. Typically, ubiquitination leads to the assembly of a K48-linked polyubiquitin chain on the substrate, which targets it for degradation by the 26S proteasome, a large multimeric proteolytic complex (Voges et al., 1999). Accordingly, defects in parkin-mediated ubiquitination have been proposed to result in the failure to target parkin substrates to the proteasome for degradation (Kahle et al., 2000;Feany and Pallanck, 2003;Giasson and Lee, 2003). 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...

show abstract

Section: Introductionmentioning

confidence: 91%

Section: Parkin Directly Binds the Synaptic Pdz Protein Pick1 Via Itsmentioning

confidence: 99%

Section: Molecular Biology Of the Cell 3112mentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

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

Joch

Ase

Chen

et al. 2007

MBoC

Self Cite

128

View full text Add to dashboard Cite

show abstract

“…Specifically, it had been shown in neurons that PARKIN (OMIM: 602544), responsible for autosomal recessive juvenile parkinsonism, interacts via its PDZ binding motif with CASK. In this report experimental data support a model whereby CASK could modulate PARKIN cellular localization, but was not directly ubiquitnated by PARKIN [27]. In contrast, PDZ proteins such as DLG1 and Scribble interact with the PDZ binding motif of the E6 protein from high-risk human papillomavirus (HPV, responsible for human cervical cancer), which acts as an E3 ligase, leading to destruction of these PDZ proteins and disorganization of epithelial structures [23].…”

Section: Discussionmentioning

confidence: 51%

DLG1 is an anchor for the E3 ligase MARCH2 at sites of cell–cell contact

Cao¹,

Huett²,

Kuballa³

et al. 2008

Cellular Signalling

View full text Add to dashboard Cite

PDZ domain containing molecular scaffolds play a central role in organizing synaptic junctions. Observations in Drosophila and mammalian cells have implicated that ubiquitination and endosomal trafficking, of molecular scaffolds are critical to the development and maintenance of cell-cell junctions and cell polarity. To elucidate if there is a connection between these pathways, we applied an integrative genomic strategy, which combined comparative genomics and proteomics with cell biological assays. Given the importance of ubiquitin in regulating endocytic processes, we first identified the subset of E3 ligases with conserved PDZ binding motifs. Among this subset, the MARCH family ubiquitin ligases account for the largest family and MARCH2 has been previously implicated in endosomal trafficking. Next, we tested in an unbiased fashion, if MARCH2 binds PDZ proteins in vivo using a modified tandem affinity purification strategy followed by mass spectrometry. Of note, DLG1 was co-purified from MARCH2, with subsequent confirmation that MARCH2 interacts with full-length DLG1 in a PDZ domain dependent manner. Furthermore, we demonstrated that MARCH2 co-localized with DLG1 at sites of cell-cell contact. In addition, loss of the MARCH2 PDZ binding motif led to loss of MARCH2 localization at cell-cell contact sites and MARCH2 appeared to localize away from cell-cell junctions. In in vivo ubiquitination assays we show that MARCH2 promotes DLG1 ubiquitination Overall, these results suggest that PDZ ligands with E3 ligase activity may link PDZ domain containing tumor suppressors to endocytic pathways and cell polarity determination.

show abstract

Parkinson Disease

Hatano

2011

Encyclopedia of Life Sciences

View full text Add to dashboard Cite

Parkinson's disease (PD) is a common movement disorder caused by loss of dopaminergic neuronal cells. The molecular mechanisms underlying neuronal degeneration in PD remain unknown; however, it is clear that genetic factors contribute to its pathogenesis. Over 15 loci and 11 causative genes have been identified so far, and many studies examine their effects on monogenic and sporadic forms of PD. Parkin mutations are the most common cause of autosomal recessive early onset PD. Parkin functions as an E3 ubiquitin ligase, which monoubiquitinates and polyubiquitinates the target proteins. Consequently, parkin participates in multiple cellular processes, such as protein degradation, mitochondrial function, endoplasmic reticulum stress, and membrane trafficking. Parkin could interact with other familial PD‐associated proteins and may share a common pathway that leads to nigral degeneration. There is evidence of a PINK1/Parkin pathway involving autophagic mitochondrial degradation. We review how parkin is associated with the pathogenesis of PD. Key Concepts: Parkinson's disease is the second most frequent neurodegenerative disease after Alzheimer's disease. Approximately 5% of patients with Parkinson's disease have a clear familial aetiology, exhibiting a classical recessive or dominant Mendelian mode of inheritance. Parkin is the most prevalent gene associated with early onset Parkinsonism, accounting for around 50% of recessive familial patients with an onset under 45 years of age. Parkin functions as an E3 ubiquitin ligase, which participates in the ubiquitin–proteasome (Ub–Pr) system. The collaboration between parkin and PINK1 promotes the autophagic degradation of damaged mitochondria. Parkin could participate in several pathways which lead to dopaminergic neuronal degeneration, such as the Ub–Pr system, autophagic protein degradation, the mitochondrial quality control system, the membrane trafficking system, and endoplasmic reticulum stress.

show abstract

Parkin and CASK/LIN-2 Associate via a PDZ-mediated Interaction and Are Co-localized in Lipid Rafts and Postsynaptic Densities in Brain

Cited by 173 publications

References 36 publications

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

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

DLG1 is an anchor for the E3 ligase MARCH2 at sites of cell–cell contact

Parkinson Disease

Contact Info

Product

Resources

About