title: Impact of p62/SQSTM1 UBA domain mutations linked to Paget's disease of bone on ubiquitin recognition.
abstract: The scaffold protein p62/SQSTM1 acts as a hub in regulating a diverse range of signaling pathways which are dependent upon a functional ubiquitin-binding C-terminal UBA domain. Mutations linked to Paget's disease of bone (PDB) commonly cluster within the UBA domain. The p62 UBA domain is unique in forming a highly stable dimer which regulates ubiquitin recognition by using overlapping surface patches in both dimerization and ubiquitin binding, making the two association events competitive. NMR structural analysis and biophysical methods show that some PDB mutations modulated the ubiquitin binding affinity by both direct and indirect mechanisms that affect UBA structural integrity, dimer stability, and contacts at the UBA-ubiquitin interface. In other cases, common PDB mutations (P392L in particular) result in no significant change in ubiquitin binding affinity for the UBA domain in isolation; however, all PDB UBA mutations lead to loss of function with respect to ubiquitin binding in the context of full-length p62, suggesting a more complex underlying mechanism.
authors.affiliation: Centre for Biomolecular Sciences, School of Chemistry, University Park, University of Nottingham, Nottingham, U.K.
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Garner
authors.forename: Jed
authors.initials: J
authors.lastname: Long
authors.forename: Robert
authors.initials: R
authors.lastname: Layfield
authors.forename: Mark S
authors.initials: MS
authors.lastname: Searle
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D019281:Dimerization; D008958:Models, Molecular; D009154:Mutation; D019906:Nuclear Magnetic Resonance, Biomolecular; D010001:Osteitis Deformans / Q000235:genetics*; D000071456:Sequestosome-1 Protein; D025801:Ubiquitin / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C099718:SQSTM1 protein, human; D000071456:Sequestosome-1 Protein; D025801:Ubiquitin