Mutant p62/SQSTM1 UBA domains linked to Paget's disease of bone differ in their abilities to function as stabilization signals.
We show that the ubiquitin-associated domain (UBA) of human p62/sequestosome-1 (SQSTM1) can delay degradation of proteasome substrates in yeast. Taking advantage of naturally occurring mutant UBA domains that are linked to Paget's disease of bone (PDB), we found that three of the four mutant UBA domains tested in this study were able to inhibit proteasomal degradation, albeit not to the same extent as the wild-type domain. Interestingly, the stability measured as the fraction of folded protein, and not the ubiquitin binding properties, of the PDB-associated UBA domains correlated with their protective effects. These data suggest that the protective effect of UBA domains depends on their structural integrity rather than ubiquitin binding capabilities.
Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden.
Christian
C
Heinen
Thomas P
TP
Garner
Jed
J
Long
Claudia
C
Böttcher
Stuart H
SH
Ralston
James R
JR
Cavey
Mark S
MS
Searle
Robert
R
Layfield
Nico P
NP
Dantuma
D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D002942:Circular Dichroism; D006207:Half-Life; D006801:Humans; D009154:Mutation; D010001:Osteitis Deformans / Q000235:genetics / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D055550:Protein Stability; D017434:Protein Structure, Tertiary; D000071456:Sequestosome-1 Protein; D013696:Temperature; D025801:Ubiquitin / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; C099718:SQSTM1 protein, human; D000071456:Sequestosome-1 Protein; D025801:Ubiquitin; D046988:Proteasome Endopeptidase Complex