Specificity in protein-ligand recognition: characterisation of a novel conformational switch in the p62 UBA domain interaction with ubiquitin

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The multi-functional p62 protein (also known as SQSTM1) regulates a diverse range of cellular processes involving in vivo interaction partners relevant to bone cell (osteoclast) and neuronal function. Mutations affecting p62 are a common cause of Paget's disease of bone (PDB), however, the precise disease mechanism in this skeletal disorder is unclear. Ubiquitin-associated (UBA) domains have been identified in many proteins as ubiquitin (Ub)-binding motifs; PDB mutations in p62 occur principally within its C-terminal UBA domain, 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. In structural studies of the UBA domain of p62 and its interaction with ubiquitin and poly-ubiquitin chains, we have recently demonstrated a novel structural re-organisation of the UBA upon binding ubiquitin that appears to provide an unique mechanism for specific regulation of ubiquitin-binding, given the participation of p62 in multiple signalling complexes. This binding mechanism suggests that PDB mutations in the UBA domain could affect ubiquitin binding specificity through both direct and indirect mechanisms that affect this conformational equilibrium. We plan to investigate the molecular origins of the interaction of much larger fragments of the p62 protein than simply the UBA domain, and investigate the underlying physiological basis for ubiquitin recognition with PDB mutations as valuable tools.