COMMD {COMM [copper metabolism Murr1 (mouse U2af1-rs1 region 1)] domain-containing} proteins participate in several cellular processes, ranging from NF-κB (nuclear factor κB) regulation, copper homoeostasis, sodium transport and adaptation to hypoxia. The best-studied member of this family is COMMD1, but relatively little is known about its regulation, except that XIAP [X-linked IAP (inhibitor of apoptosis)] functions as its ubiquitin ligase. In the present study, we identified that the COMM domain of COMMD1 is required for its interaction with XIAP, and other COMMD proteins can similarly interact with IAPs. Two conserved leucine repeats within the COMM domain were found to be critically required for XIAP binding. A COMMD1 mutant which was unable to bind to XIAP demonstrated a complete loss of basal ubiquitination and great stabilization of the protein. Underscoring the importance of IAP-mediated ubiquitination, we found that long-term expression of wild-type COMMD1 results in nearly physiological protein levels as a result of increased ubiquitination, but this regulatory event is circumvented when a mutant form that cannot bind XIAP is expressed. In summary, our findings indicate that COMMD1 expression is controlled primarily by protein ubiquitination, and its interaction with IAP proteins plays an essential role.
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Research Article|
December 23 2008
COMMD1 expression is controlled by critical residues that determine XIAP binding
Gabriel N. Maine;
Gabriel N. Maine
*Department of Internal Medicine, University of Michigan Medical School, 109 Zina Pitcher Place - SPC 2200, Ann Arbor, MI 48109, U.S.A.
†Molecular Mechanisms of Disease Program, University of Michigan Medical School, 109 Zina Pitcher Place - SPC 2200, Ann Arbor, MI 48109, U.S.A.
‡Department of Clinical Pathology, William Beaumont Hospital, 3601 West Thirteen Mile Road, Royal Oak, MI 48073, U.S.A.
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Xicheng Mao;
Xicheng Mao
*Department of Internal Medicine, University of Michigan Medical School, 109 Zina Pitcher Place - SPC 2200, Ann Arbor, MI 48109, U.S.A.
†Molecular Mechanisms of Disease Program, University of Michigan Medical School, 109 Zina Pitcher Place - SPC 2200, Ann Arbor, MI 48109, U.S.A.
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Patricia A. Muller;
Patricia A. Muller
§Laboratory of Metabolic and Endocrine Diseases, University of Utrecht, Room KC.02.069.1, Lundlaan 6, 3584 EA, Utrecht, The Netherlands
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Christine M. Komarck;
Christine M. Komarck
*Department of Internal Medicine, University of Michigan Medical School, 109 Zina Pitcher Place - SPC 2200, Ann Arbor, MI 48109, U.S.A.
†Molecular Mechanisms of Disease Program, University of Michigan Medical School, 109 Zina Pitcher Place - SPC 2200, Ann Arbor, MI 48109, U.S.A.
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Leo W. J. Klomp;
Leo W. J. Klomp
§Laboratory of Metabolic and Endocrine Diseases, University of Utrecht, Room KC.02.069.1, Lundlaan 6, 3584 EA, Utrecht, The Netherlands
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Ezra Burstein
Ezra Burstein
1
*Department of Internal Medicine, University of Michigan Medical School, 109 Zina Pitcher Place - SPC 2200, Ann Arbor, MI 48109, U.S.A.
†Molecular Mechanisms of Disease Program, University of Michigan Medical School, 109 Zina Pitcher Place - SPC 2200, Ann Arbor, MI 48109, U.S.A.
∥Gastroenterology Section at the Ann Arbor VA Medical Center, 2215 Fuller Road, Ann Arbor, MI 48105, U.S.A.
1To whom correspondence should be addressed at the present address: Department of Internal Medicine, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Room J5.126B, Dallas, TX 75390-9151, U.S.A. (email ezra.burstein@utsouthwestern.edu).
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Publisher: Portland Press Ltd
Received:
April 28 2008
Revision Received:
September 12 2008
Accepted:
September 16 2008
Accepted Manuscript online:
September 16 2008
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© The Authors Journal compilation © 2009 Biochemical Society
2009
Biochem J (2009) 417 (2): 601–609.
Article history
Received:
April 28 2008
Revision Received:
September 12 2008
Accepted:
September 16 2008
Accepted Manuscript online:
September 16 2008
Citation
Gabriel N. Maine, Xicheng Mao, Patricia A. Muller, Christine M. Komarck, Leo W. J. Klomp, Ezra Burstein; COMMD1 expression is controlled by critical residues that determine XIAP binding. Biochem J 15 January 2009; 417 (2): 601–609. doi: https://doi.org/10.1042/BJ20080854
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