Functional analyses of PDB (Paget's disease of bone)-associated mutants of the p62 [also known as SQSTM1 (sequestosome 1)] signalling adaptor protein represent an interesting paradigm for understanding not only the disease mechanism in this skeletal disorder, but also the critical determinants of ubiquitin recognition by an ubiquitin-binding protein. The 11 separate PDB mutations identified to date all affect the C-terminal region of p62 containing the UBA domain (ubiquitin-associated domain), a ubiquitin-binding element. All of these mutations have deleterious effects on ubiquitin binding by p62 in vitro, and there is evidence of an inverse relationship between ubiquitin-binding function and disease severity. The effects on ubiquitin-binding function of most of the mutations can be attributed to either reduced UBA domain stability, and/or the mutations affecting the presumed ubiquitin-binding interface of the UBA domain. However, a subset of the mutations are more difficult to rationalize; several of these affect sequences of p62 outside of the minimal ubiquitin-binding region, providing insights into non-UBA domain sequences within the host protein which mediate ubiquitin-binding affinity. The p62 mutations are presumed to result in activation of (osteoclast) NF-κB (nuclear factor κB) signalling. Understanding how loss of ubiquitin-binding function of p62 impacts on signal transduction events in osteoclasts will undoubtedly further our understanding of the disease mechanism in PDB at the molecular level.
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October 2006
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Conference Article|
October 25 2006
p62 mutations, ubiquitin recognition and Paget's disease of bone
R. Layfield;
R. Layfield
1
*School of Biomedical Sciences, University of Nottingham Medical School, Nottingham NG7 2UH, U.K.
1To whom correspondence should be addressed (email robert.layfield@nottingham.ac.uk).
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J.R. Cavey;
J.R. Cavey
*School of Biomedical Sciences, University of Nottingham Medical School, Nottingham NG7 2UH, U.K.
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D. Najat;
D. Najat
*School of Biomedical Sciences, University of Nottingham Medical School, Nottingham NG7 2UH, U.K.
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J. Long;
J. Long
†Centre for Biomolecular Sciences, School of Chemistry, University of Nottingham, Nottingham NG7 2RD, U.K.
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P.W. Sheppard;
P.W. Sheppard
‡BIOMOL International LP, Palatine House, Matford Court, Exeter EX2 8NL, U.K.
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S.H. Ralston;
S.H. Ralston
§Rheumatic Diseases Unit, University of Edinburgh, Western General Hospital, Edinburgh EH2 2XU, U.K.
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M.S. Searle
M.S. Searle
†Centre for Biomolecular Sciences, School of Chemistry, University of Nottingham, Nottingham NG7 2RD, U.K.
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Publisher: Portland Press Ltd
Received:
June 26 2006
Online ISSN: 1470-8752
Print ISSN: 0300-5127
© 2006 The Biochemical Society
2006
Biochem Soc Trans (2006) 34 (5): 735–737.
Article history
Received:
June 26 2006
Citation
R. Layfield, J.R. Cavey, D. Najat, J. Long, P.W. Sheppard, S.H. Ralston, M.S. Searle; p62 mutations, ubiquitin recognition and Paget's disease of bone. Biochem Soc Trans 1 October 2006; 34 (5): 735–737. doi: https://doi.org/10.1042/BST0340735
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