DOI: 10.1359/jbmr.041205. Loss of Ubiquitin-Binding Associated With Paget's Disease of Bone p62 (<i>SQSTM1</i>) Mutations

Loss of Ubiquitin-Binding Associated With Paget's Disease of Bone p62 (SQSTM1) Mutations

10.1359/jbmr.041205

Crossref journal-article

Oxford University Press (OUP)

Journal of Bone and Mineral Research (286)

Abstract

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.

Bibliography

Cavey, J. R., Ralston, S. H., Hocking, L. J., Sheppard, P. W., Ciani, B., Searle, M. S., & Layfield, R. (2005). Loss of Ubiquitin-Binding Associated With Pagetâs Disease of Bone p62 (SQSTM1) Mutations. Journal of Bone and Mineral Research, 20(4), 619â624.

Authors 7

James R Cavey (first)
Stuart H Ralston (additional)
Lynne J Hocking (additional)
Paul W Sheppard (additional)
Barbara Ciani (additional)
Mark S Searle (additional)
Robert Layfield (additional)

References 31 Referenced 92

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10.1002/jbmr.5650060511 / J Bone Miner Res / Familial aggregation of Paget's disease of bone by Siris (1991)
10.1136/jech.37.3.226 / J Epidemiol Community Health / A family study of Paget's disease of bone by Sofaer (1983)
10.1086/340731 / Am J Hum Genet / Recurrent mutation of the gene encoding sequestosome 1 (SQSTM1/p62) in Paget disease of bone by Laurin (2002)
10.1093/hmg/11.22.2735 / Hum Mol Genet / Domain specific mutations in Sequestosome 1 (SQSTM1) cause familial and sporadic Paget's disease by Hocking (2002)
10.1359/jbmr.2003.18.10.1748 / J Bone Miner Res / Three novel mutations in SQSTM1 identified in familial Paget's disease of bone by Johnson-Pais (2003)
10.1359/JBMR.0403015 / J Bone Miner Res / Novel UBA domain mutations of SQSTM1 in Paget's disease of bone: Genotype phenotype correlation, functional analysis and structural consequences by Hocking (2004)
10.1359/JBMR.040203 / J Bone Miner Res / Two novel mutations at exon 8 of Sequestosome 1 gene (SQSTM1) in an Italian serie of patients affected by Paget's disease of bone (PDB) by Falchetti (2004)
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Dates

Type	When
Created	19 years, 4 months ago (April 27, 2006, 3:54 a.m.)
Deposited	1 year, 5 months ago (March 13, 2024, 11:07 a.m.)
Indexed	1 month, 4 weeks ago (July 7, 2025, 5:26 a.m.)
Issued	20 years, 5 months ago (April 1, 2005)
Published	20 years, 5 months ago (April 1, 2005)
Published Online	15 years, 9 months ago (Dec. 4, 2009)
Published Print	20 years, 5 months ago (April 1, 2005)

Funders 0

None

BibTeX

@article{Cavey_2005, title={Loss of Ubiquitin-Binding Associated With Paget’s Disease of Bone p62 (SQSTM1) Mutations}, volume={20}, ISSN={1523-4681}, url={http://dx.doi.org/10.1359/jbmr.041205}, DOI={10.1359/jbmr.041205}, number={4}, journal={Journal of Bone and Mineral Research}, publisher={Oxford University Press (OUP)}, author={Cavey, James R and Ralston, Stuart H and Hocking, Lynne J and Sheppard, Paul W and Ciani, Barbara and Searle, Mark S and Layfield, Robert}, year={2005}, month=apr, pages={619–624} }

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