title: p62 mutations, ubiquitin recognition and Paget's disease of bone.
abstract: 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-kappaB (nuclear factor kappaB) 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.
authors.affiliation: School of Biomedical Sciences, University of Nottingham Medical School, Nottingham NG7 2UH, and Rheumatic Diseases Unit, University of Edinburgh, Western General Hospital, UK. robert.layfield@nottingham.ac.uk
authors.forename: R
authors.initials: R
authors.lastname: Layfield
authors.forename: J R
authors.initials: JR
authors.lastname: Cavey
authors.forename: D
authors.initials: D
authors.lastname: Najat
authors.forename: J
authors.initials: J
authors.lastname: Long
authors.forename: P W
authors.initials: PW
authors.lastname: Sheppard
authors.forename: S H
authors.initials: SH
authors.lastname: Ralston
authors.forename: M S
authors.initials: MS
authors.lastname: Searle
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D006801:Humans; D009154:Mutation; D010001:Osteitis Deformans / Q000235:genetics*; D010641:Phenotype; D011485:Protein Binding; D011506:Proteins / Q000235:genetics* / Q000378:metabolism; D000071456:Sequestosome-1 Protein; D025801:Ubiquitin / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D011506:Proteins; C099718:SQSTM1 protein, human; D000071456:Sequestosome-1 Protein; D025801:Ubiquitin