Impact of p62/SQSTM1 UBA domain mutations linked to paget's disease of bone on ubiquitin recognition

Thomas P. Garner, Jed Long, Robert Layfield, Mark S. Searle

Research output: Contribution to journalArticle

16 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)4665-4674
Number of pages10
JournalBiochemistry
Volume50
Issue number21
DOIs
StatePublished - May 31 2011
Externally publishedYes

Fingerprint

Osteitis Deformans
Ubiquitin
Bone
Mutation
Ubiquitin C
Dimers
Dimerization
Structural integrity
Scaffolds
Structural analysis
Nuclear magnetic resonance
Association reactions
Proteins

ASJC Scopus subject areas

  • Biochemistry

Cite this

Impact of p62/SQSTM1 UBA domain mutations linked to paget's disease of bone on ubiquitin recognition. / Garner, Thomas P.; Long, Jed; Layfield, Robert; Searle, Mark S.

In: Biochemistry, Vol. 50, No. 21, 31.05.2011, p. 4665-4674.

Research output: Contribution to journalArticle

Garner, Thomas P. ; Long, Jed ; Layfield, Robert ; Searle, Mark S. / Impact of p62/SQSTM1 UBA domain mutations linked to paget's disease of bone on ubiquitin recognition. In: Biochemistry. 2011 ; Vol. 50, No. 21. pp. 4665-4674.
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