Valosin-containing protein (p97/VCP) has been proposed as playing crucial roles in a variety of physiological and pathological processes such as @entity5 and @entity179 . We previously showed that VCP( @entity69457 ), an ATPase activity-negative VCP mutant, induced vacuolization, accumulation of ubiquitinated proteins, and cell death, phenotypes commonly observed in @entity179 . However, any regulatory mechanism of its ATPase activity has not yet been clarified. Here, we show that oxidative stress readily inactivates VCP ATPase activity. With liquid chromatography/tandem mass spectrometry, we found that at least three @entity462 residues were modified by oxidative stress. Of them, the 522nd @entity462 ( @entity2569 -522) was identified as the site responsible for the oxidative inactivation of VCP. VCP( @entity69458 ), a single- @entity535 substitution mutant from @entity462 to @entity1889 , conferred almost complete resistance to the oxidative inactivation. In response to oxidative stress, VCP strengthened the interaction with @entity69459 and @entity69460 , both of which are essential in endoplasmic reticulum-associated protein degradation. @entity2569 -522 is located in the second @entity855 binding motif and is highly conserved in multicellular but not unicellular organisms. @entity19976 ( @entity375 VCP) has @entity1889 in the corresponding @entity535 , and it showed resistance to the oxidative inactivation in vitro. Furthermore, a @entity375 mutant (delta @entity19976 + @entity19976 [ @entity69461 ]) was shown to be susceptible to oxidants-induced growth inhibition and cell death. These results clearly demonstrate that VCP ATPase activity is regulated by the oxidative modification of the @entity2569 -522 residue. This regulatory mechanism may play a key role in the conversion of oxidative stress to endoplasmic reticulum stress response in multicellular organisms and also in the pathological process of @entity179 .

ATPase activity of p97/valosin-containing protein is regulated by oxidative modification of the evolutionally conserved XXXX 522 residue in Walker A motif.

@entity375 :: ('4932', 'Species') :: ['yeast'] @entity462 :: ('MESH:D003545', 'Chemical') :: ['cysteine'] @entity5 :: ('MESH:D009369', 'Disease') :: ['cancer'] @entity2569 :: ('CHEBI:17561', 'Chemical') :: ['Cys'] @entity535 :: ('CHEBI:33704', 'Chemical') :: ['amino acid'] @entity69460 :: ('852939(Tax:4932)', 'Gene') :: ['Ufd1'] @entity69458 :: ('c|SUB|C|522|T', 'DNAMutation') :: ['C522T'] @entity855 :: ('MESH:D000255', 'Chemical') :: ['ATP'] @entity179 :: ('MESH:D019636', 'Disease') :: ['neurodegeneration', 'various neurodegenerative disorders', 'neurodegenerative disorders'] @entity69459 :: ('852468(Tax:4932)', 'Gene') :: ['Npl4'] @entity69461 :: ('c|SUB|T|532|C', 'DNAMutation') :: ['T532C'] @entity1889 :: ('CHEBI:26986', 'Chemical') :: ['threonine'] @entity69457 :: ('p|SUB|K|524|A', 'ProteinMutation') :: ['K524A'] @entity19976 :: ('851431(Tax:4932)', 'Gene') :: ['cdc48', 'Cdc48p']
@entity462 :: (MESH:D003545,Chemical) :: ['cysteine']
