Loss of Ubiquitin‐Binding Associated With Paget's Disease of Bone p62 (SQSTM1) Mutations (original) (raw)
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School of Biomedical Sciences, University of Nottingham, Nottingham, United Kingdom
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Department of Medicine and Therapeutics, University of Aberdeen, Aberdeen, United Kingdom
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Department of Medicine and Therapeutics, University of Aberdeen, Aberdeen, United Kingdom
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BIOMOL International LP, Exeter, United Kingdom
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Centre for Biomolecular Sciences, School of Chemistry, University of Nottingham, Nottingham, United Kingdom
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Centre for Biomolecular Sciences, School of Chemistry, University of Nottingham, Nottingham, United Kingdom
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School of Biomedical Sciences, University of Nottingham, Nottingham, United Kingdom
School of Biomedical Sciences, University of Nottingham Medical School, Nottingham NG7 2UH, UK
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Revision received:
24 September 2004
Accepted:
04 November 2004
Published:
04 December 2009
Cite
James R Cavey, Stuart H Ralston, Lynne J Hocking, Paul W Sheppard, Barbara Ciani, Mark S Searle, Robert Layfield, Loss of Ubiquitin‐Binding Associated With Paget's Disease of Bone p62 (SQSTM1) Mutations, Journal of Bone and Mineral Research, Volume 20, Issue 4, 1 April 2005, Pages 619–624, https://doi.org/10.1359/JBMR.041205
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Abstract
We have studied the effects of various PDB‐causing mutations of SQSTM1 on the in vitro ubiquitin‐binding properties of the p62 protein. All mutations caused loss of monoubiquitin‐binding and impaired K48‐linked polyubiquitin‐binding, which was only evident at physiological temperature. This suggests that SQSTM1 mutations predispose to PDB through a common mechanism that depends on loss of ubiquitin‐binding by p62.
Introduction: Mutations in the SQSTM1 gene, which affect the ubiquitin‐associated (UBA) domain of the p62 protein, are a common cause of Paget's disease of bone (PDB). We previously showed that the isolated UBA domain of p62 binds K48‐linked polyubiquitin chains in vitro and that PDB‐causing mutations in the UBA domain can be resolved in to those which retain (P392L and G411S) or lose (M404V and G425R) the ability to bind K48‐linked polyubiquitin. To further clarify the mechanisms by which these mutations predispose to PDB, we have extended these analyses to study the ubiquitin‐binding properties of the PDB‐causing mutations in the context of the full‐length p62 protein.
Materials and Methods: We studied the effects of various PDB‐causing mutations on the interaction between glutathione _S_‐transferase (GST)‐tagged p62 proteins and monoubiquitin, as well as K48‐linked polyubiquitin chains, using in vitro ubiquitin‐binding assays.
Results: All of the PDB‐causing mutations assessed (P392L, E396X, M404V, G411S, and G425R) caused loss of monoubiquitin binding and impaired K48‐linked polyubiquitin‐binding when introduced into the full‐length p62 protein. However, these effects were only observed when the binding experiments were conducted at physiological temperature (37°C); they were not seen at room temperature or at 4°C.
Conclusions: Our in vitro findings suggest that PDB‐causing mutations of SQSTM1 could predispose to disease through a common mechanism that is dependent on impaired binding of p62 to a ubiquitylated target and show that 5q35‐linked PDB is the first example of a human disorder caused by loss of function mutations in a UBA domain.
Copyright © 2005 ASBMR
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