Journal article
Paget disease of bone-associated UBA domain mutations of SQSTM1 exert distinct effects on protein structure and function
Biochimica et biophysica acta. Molecular basis of disease, Vol.1842(7), pp.992-1000
2014
PMID: 24642144
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-kappa B 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-kappa B 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-kappa B 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. (C) 2014 The Authors. Published by Elsevier B.V.
Details
- Title
- Paget disease of bone-associated UBA domain mutations of SQSTM1 exert distinct effects on protein structure and function
- Authors/Creators
- Alice Goode - University of NottinghamJed E. Long - University of NottinghamBarry Shaw - University of NottinghamStuart H. Ralston - Western General HospitalMicaela Rios Visconti - Western General HospitalFernando Gianfrancesco - Institute of Genetics and BiophysicsTeresa Esposito - Institute of Genetics and BiophysicsLuigi Gennari - University of SienaDaniela Merlotti - University of SienaDomenico Rendina - Federico II University HospitalSarah L. Rea - Harry Perkins Institute of Medical ResearchMelanie Sultana - Sir Charles Gairdner HospitalMark S. Searle - University of NottinghamRobert Layfield - University of Nottingham
- Publication Details
- Biochimica et biophysica acta. Molecular basis of disease, Vol.1842(7), pp.992-1000
- Publisher
- Elsevier B.V.
- Number of pages
- 9
- Grant note
- 18585; 19799 / Arthritis Research UK; Versus Arthritis 18585; 19799 / Versus Arthritis BB/I011420/1 / Biotechnology and Biological Sciences Research Council; UK Research & Innovation (UKRI); Biotechnology and Biological Sciences Research Council (BBSRC) BB/I011420/1 / BBSRC; UK Research & Innovation (UKRI); Biotechnology and Biological Sciences Research Council (BBSRC) GGP11119 / Telethon grant; Fondazione Telethon APP1027932 / National Health and Medical Research Council of Australia; National Health and Medical Research Council (NHMRC) of Australia JEL
- Identifiers
- 991005616396007891
- Copyright
- © 2014 The Authors.
- Murdoch Affiliation
- Centre for Molecular Medicine and Innovative Therapeutics
- Language
- English
- Resource Type
- Journal article
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- 1 Clinical & Life Sciences
- 1.80 Bone Diseases
- 1.80.1211 Bisphosphonates
- Web Of Science research areas
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- Biophysics
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- ESI research areas
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