GONUTS has been updated to MW1.31 Most things seem to be working but be sure to report problems.

Have any questions? Please email us at ecoliwiki@gmail.com

PMID:17553932

From GONUTS
Jump to: navigation, search
Citation

Joch, M, Ase, AR, Chen, CX, MacDonald, PA, Kontogiannea, M, Corera, AT, Brice, A, Séguéla, P and Fon, EA (2007) Parkin-mediated monoubiquitination of the PDZ protein PICK1 regulates the activity of acid-sensing ion channels. Mol. Biol. Cell 18:3105-18

Abstract

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 ubiquitin-ligase-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.

Links

PubMed PMC1949385 Online version:10.1091/mbc.E05-11-1027

Keywords

Amino Acids; Animals; COS Cells; Carrier Proteins/metabolism; Cercopithecus aethiops; HeLa Cells; Humans; Ion Channel Gating; Membrane Proteins/metabolism; Mice; Nerve Tissue Proteins/metabolism; Neurons/enzymology; Nuclear Proteins/metabolism; Proteasome Endopeptidase Complex/metabolism; Protein Binding; Protein Processing, Post-Translational; Protein Transport; Rats; Sodium Channels/metabolism; Subcellular Fractions/metabolism; Substrate Specificity; Ubiquitin/metabolism; Ubiquitin-Protein Ligases/metabolism

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

MOUSE:PRKN2

GO:0031398: positive regulation of protein ubiquitination

ECO:0000314:

P

Figure 4: Parkin (E3 ubiquitin-ligase) binds PICK1 protein which mediates and promotes monoubiquitination of PICK1.

complete
CACAO 3587


See also

References

See Help:References for how to manage references in GONUTS.