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Parkin Mediates Nonclassical, Proteasomal-Independent Ubiquitination of Synphilin-1: Implications for Lewy Body Formation
Abstract
It is widely accepted that the familial Parkinson's disease (PD)-linked gene product, parkin, functions as a ubiquitin ligase involved in protein turnover via the ubiquitin-proteasome system. Substrates ubiquitinated by parkin are hence thought to be destined for proteasomal degradation. Because we demonstrated previously that parkin interacts with and ubiquitinates synphilin-1, we initially expected synphilin-1 degradation to be enhanced in the presence of parkin. Contrary to our expectation, we found that synphilin-1 is normally ubiquitinated by parkin in a nonclassical, proteasomal-independent manner that involves lysine 63 (K63)-linked polyubiquitin chain formation. Parkin-mediated degradation of synphilin-1 occurs appreciably only at an unusually high parkin to synphilin-1 expression ratio or when primed for lysine 48 (K48)-linked ubiquitination. In addition we found that parkin-mediated ubiquitination of proteins within Lewy-body-like inclusions formed by the coexpression of synphilin-1, α-synuclein, and parkin occurs predominantly via K63 linkages and that the formation of these inclusions is enhanced by K63-linked ubiquitination. Our results suggest that parkin is a dual-function ubiquitin ligase and that K63-linked ubiquitination of synphilin-1 by parkin may be involved in the formation of Lewy body inclusions associated with PD.
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Parkin has been reported previously to conjugate Ub linked via K48, K63, K27, and K29 as well as linear Ub chains and mono-Ub.
“Parkin has been reported previously to conjugate Ub linked via a number of different lysines including K48, K63, K27, and K29 as well as linear Ub chains and mono-Ub”
From USP8 regulates mitophagy by removing K6‐linked ubiquitin conjugates from parkin (2014) · cites this paper as Lim et al, 2005
In the section on parkin-mediated autoubiquitination and synphilin-1 ubiquitination via K63-linked chains (page unavailable), the paper reports parkin-mediated K48- and K63-linked ubiquitination. The passages do not report parkin conjugating K27- or K29-linked ubiquitin, linear chains, or mono-ubiquitin. (LLM, conf=0.87)
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Familial Parkinson disease gene product, parkin, is a ubiquitin-protein ligase
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“We and others initially elucidated the function of parkin as a ubiquitin ligase and showed that pathological mutations of parkin impair its catalytic activity (Imai et al., 2000; Shimura et al., 2000; Zhang et al., 2000).”
BackgroundA multiubiquitin chain is confined to specific lysine in a targeted short-lived protein
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Metadata
- Authors
- Lim, K. L., Chew, K. C. M., Tan, J. M. M., Wang, C., Chung, K. K. K., Zhang, Y., Tanaka, Y., Smith, W., Engelender, S., Ross, C. A., Dawson, V. L., & Dawson, T. M.
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2005-02-23
- Volume
- 25
- Issue
- 8
- Pages
- 2002-2009
- ISSN
- 0270-6474
- 1529-2401
- Cited by
- 503
- References
- 4
- Language
- en
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