The effects of the polyglutamine repeat protein ataxin-1 on the UbL-UBA protein A1Up.
The ataxin-1 interacting ubiquitin-like protein (A1Up) contains an amino-terminal ubiquitin-like (UbL) region, four stress-inducible, heat shock chaperonin-binding motifs (STI1), and an ubiquitin-associated domain (UBA) at the carboxyl terminus of A1Up. Although proteins that have both an UbL and UBA domain are thought to play a crucial role in proteasome-mediated activities, few are characterized, except for hHR23A/B. Similar to other UbL-containing proteins, the UbL of A1Up is essential for the interaction of A1Up with the S5a subunit of the 19S proteasome. Importantly, the interaction with the 19S proteasome was disrupted in the presence of the polyglutamine repeat protein, ataxin-1. The UbL domain of A1Up is ubiquitinated by both Lys(48)-linked and Lys(63)-linked chains. Intact A1Up is stable, suggesting that ubiquitination of A1Up is important for degradation-independent targeting of A1Up to the 19S proteasome. The UBA domain of A1Up binds polyubiquitin chains and has a role in the stability of A1Up and in the subcellular localization of A1Up. When the UBA domain was deleted, the localization of A1Up was entirely cytoplasmic, and it co-localized with the proteasome. Interestingly, the interaction between A1Up and mutant ataxin-1-(82Q) increased the half-life of A1Up, whereas nonpathogenic wild-type ataxin-1-(30Q) or ataxin-1-(82Q)-A776 did not.
Department of Biochemistry, Institute of Human Genetics, University of Minnesota, Minneapolis, Minnesota 55455, USA.
Brigit E
BE
Riley
Yifan
Y
Xu
Huda Y
HY
Zoghbi
Harry T
HT
Orr
D000818:Animals; D000067696:Ataxin-1; D000067528:Ataxins; D002352:Carrier Proteins / Q000737:chemistry / Q000378:metabolism*; D002460:Cell Line; D003546:Cysteine Endopeptidases / Q000378:metabolism; D009097:Multienzyme Complexes / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism / Q000502:physiology*; D009687:Nuclear Proteins / Q000737:chemistry / Q000378:metabolism* / Q000502:physiology*; D010455:Peptides; D046988:Proteasome Endopeptidase Complex; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D021381:Protein Transport; D014162:Transfection; D025801:Ubiquitin / Q000378:metabolism
C000593749:ATXN1 protein, human; D000067696:Ataxin-1; D000067528:Ataxins; D002352:Carrier Proteins; D009097:Multienzyme Complexes; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D010455:Peptides; C421907:UBQLN4 protein, human; D025801:Ubiquitin; C097188:polyglutamine; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex