Regulation of Torsin ATPases by LAP1 and LULL1

Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06520-8114.
Proceedings of the National Academy of Sciences (Impact Factor: 9.81). 04/2013; 110(17). DOI: 10.1073/pnas.1300676110
Source: PubMed

ABSTRACT TorsinA is a membrane-associated AAA+ (ATPases associated with a variety of cellular activities) ATPase implicated in primary dystonia, an autosomal-dominant movement disorder. We reconstituted TorsinA and its cofactors in vitro and show that TorsinA does not display ATPase activity in isolation; ATP hydrolysis is induced upon association with LAP1 and LULL1, type II transmembrane proteins residing in the nuclear envelope and endoplasmic reticulum. This interaction requires TorsinA to be in the ATP-bound state, and can be attributed to the luminal domains of LAP1 and LULL1. This ATPase activator function controls the activities of other members of the Torsin family in distinct fashion, leading to an acceleration of the hydrolysis step by up to two orders of magnitude. The dystonia-causing mutant of TorsinA is defective in this activation mechanism, suggesting a loss-of-function mechanism for this congenital disorder.

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