ArticleBiochimica et biophysica acta2014
Paget disease of bone-associated UBA domain mutations of SQSTM1 exert distinct effects on protein structure and function.
Article in Biochimica et biophysica acta, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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Who cites it
18 citing papers in PubMed, 31 citations in OpenAlex.
- Standard and advanced echocardiographic study of patients with Paget's disease of bone: Evidence of a pagetic heart disease?Journal of internal medicine · 2025Article
- Update on the pathogenesis and genetics of Paget's disease of bone.Frontiers in cell and developmental biology · 2022Review
- TFEB phosphorylation on Serine 211 is induced by autophagy in human synovial fibroblasts and by p62/SQSTM1 overexpression in HEK293 cells.The Biochemical journal · 2021Article
- Paget's disease of bone: Report of 11 cases.World journal of clinical cases · 2021Article
- The high stability of the three-helix bundle UBA domain of p62 protein as revealed by molecular dynamics simulations.Journal of molecular modeling · 2021Article
- Adult Paget's disease of bone.Clinical medicine (London, England) · 2020Article
- Molecular insights into an ancient form of Paget's disease of bone.Proceedings of the National Academy of Sciences of the United States of America · 2019Article
- Paget's Disease of Bone.Calcified tissue international · 2019Review
- Review
- Article
- Clinical and Genetic Advances in Paget's Disease of Bone: a Review.Clinical reviews in bone and mineral metabolism · 2017Review
- ALS-FTLD associated mutations of SQSTM1 impact on Keap1-Nrf2 signalling.Molecular and cellular neurosciences · 2016Article
- Defective recognition of LC3B by mutant SQSTM1/p62 implicates impairment of autophagy as a pathogenic mechanism in ALS-FTLD.Autophagy · 2016Article
- p62 links the autophagy pathway and the ubiqutin-proteasome system upon ubiquitinated protein degradation.Cellular & molecular biology letters · 2016Review
- Paget's disease of bone-genetic and environmental factors.Nature reviews. Endocrinology · 2015Review
- Selective autophagic receptor p62 regulates the abundance of transcriptional coregulator ARIP4 during nutrient starvation.Scientific reports · 2015Article
- Paget's sarcoma of the patella.Skeletal radiology · 2015Article
- Genetics of Paget's disease of bone.Current osteoporosis reports · 2014Review
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Authors and funding
14 authors at 7 institutions in 3 countries.
Funding
Abstract
SQSTM1 mutations are common in patients with Paget disease of bone (PDB), with most affecting the C-terminal ubiquitin-associated (UBA) domain of the SQSTM1 protein. We performed structural and functional analyses of two UBA domain mutations, an I424S mutation relatively common in UK PDB patients, and an A427D mutation associated with a severe phenotype in Southern Italian patients. Both impaired SQSTM1's ubiquitin-binding function in pull-down assays and resulted in activation of basal NF-κB signalling, compared to wild-type, in reporter assays. We found evidence for a relationship between the ability of different UBA domain mutants to activate NF-κB signalling in vitro and number of affected sites in vivo in 1152 PDB patients from the UK and Italy, with A427D-SQSTM1 producing the greatest level of activation (relative to wild-type) of all PDB mutants tested to date. NMR and isothermal titration calorimetry studies were able to demonstrate that I424S is associated with global structural changes in the UBA domain, resulting in 10-fold weaker UBA dimer stability than wild-type and reduced ubiquitin-binding affinity of the UBA monomer. Our observations provide insights into the role of SQSTM1-mediated NF-κB signalling in PDB aetiology, and demonstrate that different mutations in close proximity within loop 2/helix 3 of the SQSTM1 UBA domain exert distinct effects on protein structure and stability, including indirect effects at the UBA/ubiquitin-binding interface.
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