Skip Navigation


Human Molecular Genetics Advance Access originally published online on October 14, 2003
This Article
Right arrow Full Text Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow All Versions of this Article:
12/23/3195    most recent
ddg344v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrow Search for citing articles in:
ISI Web of Science (72)
Right arrowRequest Permissions
Google Scholar
Right arrow Articles by Burnett, B.
Right arrow Articles by Pittman, R. N.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Burnett, B.
Right arrow Articles by Pittman, R. N.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

Human Molecular Genetics, 2003, Vol. 12, No. 23 3195-3205
DOI: 10.1093/hmg/ddg344
© 2003 Oxford University Press

The polyglutamine neurodegenerative protein ataxin-3 binds polyubiquitylated proteins and has ubiquitin protease activity

Barrington Burnett{dagger}, Fusheng Li{dagger} and Randall N. Pittman*

Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104-6084, USA

Received September 9, 2003; Accepted October 2, 2003

The ubiquitin-proteasome pathway is critically involved in the pathology of neurodegenerative diseases characterized by protein misfolding and aggregation. Data in the present study suggest that the polyglutamine neurodegenerative disease protein, ataxin-3 (AT3), functions in the ubiquitin-proteasome pathway. AT3 contains an ubiquitin interaction motif (UIM) domain that binds polyubiquitylated proteins with a strong preference for chains containing four or more ubiquitins. Mutating the conserved leucine in the first UIM (L229A) almost totally eliminates binding to polyubiquitin chains while a similar mutation in the second UIM (L249A) also inhibits binding to polyubiquitin chains but to a lesser extent. Both wild-type and pathological AT3 increase cellular levels of a short-lived GFP that is degraded by the ubiquitin-proteasome pathway. AT3 has several properties characteristic of ubiquitin proteases including decreasing polyubiquitylation of 125I-lysozyme by removing ubiquitin from polyubiquitin chains, cleaving a ubiquitin protease substrate, and binding the specific ubiquitin protease inhibitor, ubiquitin-aldehyde. Mutating the predicted catalytic cysteine in AT3 inhibits each of these ubiquitin protease activities. The ability to bind and cleave ubiquitylated proteins is consistent with AT3 playing a role in the ubiquitin-proteasome system. This raises the possibility that pathological AT3, which tends to misfold and aggregate, may be exposed to aggregate-prone misfolded/denatured proteins as part of its normal function.

* To whom correspondence should be addressed. Tel: +1 2158989736; Fax: +1 2155732236; Email: pittman{at}pharm.med.upenn.edu

{dagger} The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.


Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?


This article has been cited by other articles:


Home page
 J. Biol. Chem.Home page
B. J. Winborn, S. M. Travis, S. V. Todi, K. M. Scaglione, P. Xu, A. J. Williams, R. E. Cohen, J. Peng, and H. L. Paulson
The Deubiquitinating Enzyme Ataxin-3, a Polyglutamine Disease Protein, Edits Lys63 Linkages in Mixed Linkage Ubiquitin Chains
J. Biol. Chem., September 26, 2008; 283(39): 26436 - 26443.
[Abstract] [Full Text] [PDF]

Home page
 Hum Mol GenetHome page
S. Alves, E. Regulier, I. Nascimento-Ferreira, R. Hassig, N. Dufour, A. Koeppen, A. L. Carvalho, S. Simoes, M. C. P. de Lima, E. Brouillet, et al.
Striatal and nigral pathology in a lentiviral rat model of Machado-Joseph disease
Hum. Mol. Genet., July 15, 2008; 17(14): 2071 - 2083.
[Abstract] [Full Text] [PDF]

Home page
 NeuroscientistHome page
J. Gardiner, D. Barton, J. May Vanslambrouck, F. Braet, D. Hall, J. Marc, and R. Overall
Defects in Tongue Papillae and Taste Sensation Indicate a Problem with Neurotrophic Support in Various Neurological Diseases
Neuroscientist, June 1, 2008; 14(3): 240 - 250.
[Abstract] [PDF]

Home page
 J. Biol. Chem.Home page
Q. Wang, L. Li, and Y. Ye
Inhibition of p97-dependent Protein Degradation by Eeyarestatin I
J. Biol. Chem., March 21, 2008; 283(12): 7445 - 7454.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
L.-B. Li, K. Xu, and N. M. Bonini
Suppression of Polyglutamine Toxicity by the Yeast Sup35 Prion Domain in Drosophila
J. Biol. Chem., December 28, 2007; 282(52): 37694 - 37701.
[Abstract] [Full Text] [PDF]

Home page
 Hum Mol GenetHome page
J. Shao and M. I. Diamond
Polyglutamine diseases: emerging concepts in pathogenesis and therapy
Hum. Mol. Genet., October 15, 2007; 16(R2): R115 - R123.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
S. V. Todi, M. N. Laco, B. J. Winborn, S. M. Travis, H. M. Wen, and H. L. Paulson
Cellular Turnover of the Polyglutamine Disease Protein Ataxin-3 Is Regulated by Its Catalytic Activity
J. Biol. Chem., October 5, 2007; 282(40): 29348 - 29358.
[Abstract] [Full Text] [PDF]

Home page
 J. Neurosci.Home page
U. Bichelmeier, T. Schmidt, J. Hubener, J. Boy, L. Ruttiger, K. Habig, S. Poths, M. Bonin, M. Knipper, W. J. Schmidt, et al.
Nuclear Localization of Ataxin-3 Is Required for the Manifestation of Symptoms in SCA3: In Vivo Evidence
J. Neurosci., July 11, 2007; 27(28): 7418 - 7428.
[Abstract] [Full Text] [PDF]

Home page
 FASEB J.Home page
A.-J. Rodrigues, G. Coppola, C. Santos, M. d. C. Costa, M. Ailion, J. Sequeiros, D. H. Geschwind, and P. Maciel
Functional genomics and biochemical characterization of the C. elegans orthologue of the Machado-Joseph disease protein ataxin-3
FASEB J, April 1, 2007; 21(4): 1126 - 1136.
[Abstract] [Full Text] [PDF]

Home page
 Pharmacol. Rev.Home page
J. J. Yi and M. D. Ehlers
Emerging Roles for Ubiquitin and Protein Degradation in Neuronal Function
Pharmacol. Rev., March 1, 2007; 59(1): 14 - 39.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
S. H. Kang, G. R. Kim, M. Seong, S. H. Baek, J. H. Seol, O. S. Bang, H. Ovaa, K. Tatsumi, M. Komatsu, K. Tanaka, et al.
Two Novel Ubiquitin-fold Modifier 1 (Ufm1)-specific Proteases, UfSP1 and UfSP2
J. Biol. Chem., February 23, 2007; 282(8): 5256 - 5262.
[Abstract] [Full Text] [PDF]

Home page
 J. Neurosci.Home page
B. O. Evert, J. Araujo, A. M. Vieira-Saecker, R. A. I. de Vos, S. Harendza, T. Klockgether, and U. Wullner
Ataxin-3 Represses Transcription via Chromatin Binding, Interaction with Histone Deacetylase 3, and Histone Deacetylation.
J. Neurosci., November 1, 2006; 26(44): 11474 - 11486.
[Abstract] [Full Text] [PDF]

Home page
 J. Cell Biol.Home page
Q. Wang, L. Li, and Y. Ye
Regulation of retrotranslocation by p97-associated deubiquitinating enzyme ataxin-3
J. Cell Biol., September 25, 2006; 174(7): 963 - 971.
[Abstract] [Full Text] [PDF]

Home page
 Hum Mol GenetHome page
X. Zhong and R. N. Pittman
Ataxin-3 binds VCP/p97 and regulates retrotranslocation of ERAD substrates
Hum. Mol. Genet., August 15, 2006; 15(16): 2409 - 2420.
[Abstract] [Full Text] [PDF]

Home page
 Genes Dev.Home page
B. E. Riley and H. T Orr
Polyglutamine neurodegenerative diseases and regulation of transcription: assembling the puzzle.
Genes & Dev., August 15, 2006; 20(16): 2183 - 2192.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
A. M. Ellisdon, B. Thomas, and S. P. Bottomley
The Two-stage Pathway of Ataxin-3 Fibrillogenesis Involves a Polyglutamine-independent Step
J. Biol. Chem., June 23, 2006; 281(25): 16888 - 16896.
[Abstract] [Full Text] [PDF]

Home page
 Hum Mol GenetHome page
A. Haacke, S. A. Broadley, R. Boteva, N. Tzvetkov, F. U. Hartl, and P. Breuer
Proteolytic cleavage of polyglutamine-expanded ataxin-3 is critical for aggregation and sequestration of non-expanded ataxin-3
Hum. Mol. Genet., February 15, 2006; 15(4): 555 - 568.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
S. J. S. Berke, Y. Chai, G. L. Marrs, H. Wen, and H. L. Paulson
Defining the Role of Ubiquitin-interacting Motifs in the Polyglutamine Disease Protein, Ataxin-3
J. Biol. Chem., September 9, 2005; 280(36): 32026 - 32034.
[Abstract] [Full Text] [PDF]

Home page
 Proc. Natl. Acad. Sci. USAHome page
Y. Mao, F. Senic-Matuglia, P. P. Di Fiore, S. Polo, M. E. Hodsdon, and P. De Camilli
Deubiquitinating function of ataxin-3: Insights from the solution structure of the Josephin domain
PNAS, September 6, 2005; 102(36): 12700 - 12705.
[Abstract] [Full Text] [PDF]

Home page
 Genome ResHome page
K. K. Kojima and H. Fujiwara
An extraordinary retrotransposon family encoding dual endonucleases
Genome Res., August 1, 2005; 15(8): 1106 - 1117.
[Abstract] [Full Text] [PDF]

Home page
 Proc. Natl. Acad. Sci. USAHome page
G. Nicastro, R. P. Menon, L. Masino, P. P. Knowles, N. Q. McDonald, and A. Pastore
The solution structure of the Josephin domain of ataxin-3: Structural determinants for molecular recognition
PNAS, July 26, 2005; 102(30): 10493 - 10498.
[Abstract] [Full Text] [PDF]

Home page
 Proc. Natl. Acad. Sci. USAHome page
B. G. Burnett and R. N. Pittman
The polyglutamine neurodegenerative protein ataxin 3 regulates aggresome formation
PNAS, March 22, 2005; 102(12): 4330 - 4335.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
M. K. M. Chow, A. M. Ellisdon, L. D. Cabrita, and S. P. Bottomley
Polyglutamine Expansion in Ataxin-3 Does Not Affect Protein Stability: IMPLICATIONS FOR MISFOLDING AND DISEASE
J. Biol. Chem., November 12, 2004; 279(46): 47643 - 47651.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
B. E. Riley, Y. Xu, H. Y. Zoghbi, and H. T. Orr
The Effects of the Polyglutamine Repeat Protein Ataxin-1 on the UbL-UBA Protein A1Up
J. Biol. Chem., October 1, 2004; 279(40): 42290 - 42301.
[Abstract] [Full Text] [PDF]

Home page
 Protein Eng Des SelHome page
T. Tenno, N. Goda, Y. Tateishi, H. Tochio, M. Mishima, H. Hayashi, M. Shirakawa, and H. Hiroaki
High-throughput construction method for expression vector of peptides for NMR study suited for isotopic labeling
Protein Eng. Des. Sel., April 1, 2004; 17(4): 305 - 314.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
Y. Chai, S. S. Berke, R. E. Cohen, and H. L. Paulson
Poly-ubiquitin Binding by the Polyglutamine Disease Protein Ataxin-3 Links Its Normal Function to Protein Surveillance Pathways
J. Biol. Chem., January 30, 2004; 279(5): 3605 - 3611.
[Abstract] [Full Text] [PDF]


Disclaimer:
Please note that abstracts for content published before 1996 were created through digital scanning and may therefore not exactly replicate the text of the original print issues. All efforts have been made to ensure accuracy, but the Publisher will not be held responsible for any remaining inaccuracies. If you require any further clarification, please contact our Customer Services Department.