The p62 protein functions as a scaffold in signalling pathways that lead to activation of NF-B, and is an important regulator of osteo-clastogenesis. Mutations affecting the RANK-NF-B signalling axis can result in human skeletal disorders, including those identified in the C-terminal ubiquitin associated (UBA) domain of p62 in patients with Paget’s disease of bone. These observations suggest that the disease may involve a common mechanism related to alterations in the Ub-binding properties of p62. The structural basis for ubiquitin recognition by the UBA domain of p62 has been investigated using NMR and reveals a novel binding mechanism involving a slow-exchange structural reorganisation of the UBA domain to a “bound” non-canonical UBA conformation that is not significantly populated in the absence of ubiquitin. The repacking of the three-helix bundle generates a binding surface localised around the conserved Xaa-Gly-Phe-Xaa loop that appears to optimise both hydrophobic and electrostatic surface complementarity with ubiquitin. NMR titration analysis shows that the p62-UBA binds to Lys48-linked diUb with ~4-fold lower affinity than to mUb, suggesting preferential binding of the p62-UBA to single ubiquitin units, consistent with the apparent in vivo preference of the p62 protein for Lys63-linked poly-ubiquitin chains (which adopt a more open and extended structure). The conformational switch observed on binding may represent a novel mechanism that underlies specificity in regulating signal-induced protein recognition events.