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Dynamic functional assembly of the Torsin AAA+ ATPase and its modulation by LAP1: a novel mode of regulation for AAA+ ATPases
Author(s) -
Chase A. R.,
Laudermilch E. R.,
Wang J.,
Shigematsu H.,
Yokoyama T. R.,
Schlieker C.
Publication year - 2018
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2018.32.1_supplement.114.1
Subject(s) - cofactor , aaa proteins , atp hydrolysis , atpase , microbiology and biotechnology , v atpase , biology , biochemistry , chemistry , enzyme
TorsinA is an essential AAA+ ATPase requiring LAP1 or LULL1 as cofactors. The dynamics of the Torsin/cofactor system remain poorly understood, with previous models invoking Torsin/cofactor assemblies with fixed stoichiometries. Here we demonstrate that TorsinA assembles into homotypic oligomers in the presence of ATP. Torsin variants mutated at the “back” interface disrupt homo‐oligomerization but still show robust ATPase activity in the presence of its cofactors. These Torsin mutants are severely compromised in their ability to rescue nuclear envelope defects in Torsin‐deficient cells, suggesting that TorsinA homo‐oligomers play a key role in vivo. Engagement of the oligomer by LAP1 triggers ATP hydrolysis and rapid complex disassembly. Thus the Torsin complex is a highly dynamic assembly whose oligomeric state is tightly controlled by distinctively localized cellular cofactors. Our discovery that LAP1 serves as a modulator of the oligomeric state of an AAA+ protein establishes a novel means of regulating this important class of oligomeric ATPases. Notably, both the homo‐oligomerization and the ATPase activation are offset by a TorsinA mutation implicated in the movement disorder DYT1 dystonia, possibly contributing to the molecular etiology of this disease. Support or Funding Information Dystonia Medical FoundationNIH NIGMS This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .