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PMID: 21466165 Published · ppublish English Journal Article Research Support, N.I.H., Extramural

Ubiquitin ligase parkin promotes Mdm2-arrestin interaction but inhibits arrestin ubiquitination.

Biochemistry ·Vol. 50 ·No. 18 ·2011-05-10 ·Pages 3749-63

Ahmed MR, Zhan X, Song X, Kook S, Gurevich VV, Gurevich EV

Abstract

Numerous mutations in E3 ubiquitin ligase parkin were shown to associate with familial Parkinson's disease. Here we show that parkin binds arrestins, versatile regulators of cell signaling. Arrestin-parkin interaction was demonstrated by coimmunoprecipitation of endogenous proteins from brain tissue and shown to be direct using purified proteins. Parkin binding enhances arrestin interactions with another E3 ubiquitin ligase, Mdm2, apparently by shifting arrestin conformational equilibrium to the basal state preferred by Mdm2. Although Mdm2 was reported to ubiquitinate arrestins, parkin-dependent increase in Mdm2 binding dramatically reduces the ubiquitination of both nonvisual arrestins, basal and stimulated by receptor activation, without affecting receptor internalization. Several disease-associated parkin mutations differentially affect the stimulation of Mdm2 binding. All parkin mutants tested effectively suppress arrestin ubiquitination, suggesting that bound parkin shields arrestin lysines targeted by Mdm2. Parkin binding to arrestins along with its effects on arrestin interaction with Mdm2 and ubiquitination is a novel function of this protein with implications for Parkinson's disease pathology.

MeSH Terms
Animals Arrestin/chemistry Dose-Response Relationship, Drug HeLa Cells Humans Lysine/chemistry Mice Parkinson Disease/metabolism Protein Binding Proto-Oncogene Proteins c-mdm2/chemistry Rabbits Spectrometry, Fluorescence/methods Ubiquitin/chemistry Ubiquitin-Protein Ligases/chemistry
Chemicals
Arrestin Ubiquitin MDM2 protein, human Proto-Oncogene Proteins c-mdm2 Ubiquitin-Protein Ligases parkin protein Lysine
Authors & Affiliations
6 authors, click to expand affiliations / ORCID
Ahmed M Rafiuddin
Department of Pharmacology, Vanderbilt University, Nashville, Tennessee 37232, USA.
Zhan Xuanzhi
Song Xiufeng
Kook Seunghyi
Gurevich Vsevolod V
Gurevich Eugenia V
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Article Info
Journal
Biochemistry
Abbr.
Biochemistry
ISSN
1520-4995
DOI
10.1021/bi200175q
Published
2011-05-10
Epub
2011-00-12
Pages
3749-63
Language
English
Region
United States
NLM ID
0370623
PMCID
PMC3091828
Subset
IM
Grants
NINDS NIH HHS · R01 NS045117-01A1 · United States
NIGMS NIH HHS · GM081756 · United States
NEI NIH HHS · EY01500 · United States
NIGMS NIH HHS · R01 GM077561 · United States
NIGMS NIH HHS · R01 GM081756 · United States
NINDS NIH HHS · NS065868 · United States
NINDS NIH HHS · NS045117 · United States
NIGMS NIH HHS · GM077561 · United States
NINDS NIH HHS · R01 NS045117 · United States
NEI NIH HHS · R01 EY011500 · United States
NINDS NIH HHS · R01 NS065868-01 · United States
NINDS NIH HHS · R01 NS065868 · United States
External Links
PubMed source DOI: 10.1021/bi200175q PMC Full Text View journal details
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