Structural role of a unique p62 UBA dimer in the regulation of signal transduction and autophagy

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p62 is a multi-functional scaffold protein (also known as SQSTM1) which regulates a diverse range of cellular processes involving in vivo interaction partners relevant to bone cell (osteoclast), neuronal function and autophagetic clearance of protein aggregates from cells. Mutations in p62 are a common cause of Paget's disease of bone (PDB), however, the precise disease mechanism in this skeletal disorder is unclear. P62 is a ubiquitin-binding receptor and uses a UBA domain to achieve binding and recognition of ubiquitin. PDB mutations in p62 occur principally within the UBA recognition motif of p62, with the implication that these pathological mutations may compromise interactions of the p62 protein with osteoclast protein targets already tagged with ubiquitin. More recently, mutations in other parts of the p62 sequence have been identified in PDB patients which still result in loss or impairment of ubiquitin-binding function. We have recently demonstrated that the UBA domain of p62 is unique amongst this family of ubiquitin binding domains (UBDs) in forming a highly stable 'biologically inactive' dimer which appears to regulate the binding to poly-ubiquitin chains. The stability of the dimer also appears to be directly correlated with levels of NF-kB signalling activity in osteoclasts, linked to bone metabolism. Given the participation of p62 in multiple signalling complexes, the stability of the UBA dimer and the subsequent effects of PDB mutations will be investigated at the molecular and structural level to shed light on the physiological relevance of the formation of the p62 UBA dimer on p62's mode of action and the possible links to dysfunctional regulation of protein-protein interactions and human disease that result from mutations within the p62 receptor.