Paget disease of bone-associated UBA domain mutations of SQSTM1 exert distinct effects on protein structure and function.

However, repeating this analysis with every patient in the study population assigned a NF-κB score according to mutation status (which makes use of all study data) and relating this to affected bone numbers, the result was highly significant both when we included all patients (r = 0.277, p < 0.0001) and also when the two patients with A427D mutations were excluded (r = 0.244, p < 0.001) (data not shown). 3.4 Impact of mutations on UBA domain structure and dimerisation We next sought to understand the structural basis of the effects of the I424S and A427D mutants on SQSTM1's ubiquitin-binding function revealed in the pull-down assays ( Fig. 1 b), and in particular, given the close proximity of these mutations to the site affected by the previously characterised G425R mutant, whether common or distinct mechanisms are manifested.

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