TorsinA in the nuclear envelope

Proc Natl Acad Sci U S A. 2004 May 18;101(20):7612-7. doi: 10.1073/pnas.0308760101. Epub 2004 May 10.


Early-onset torsion dystonia, a CNS-based movement disorder, is usually associated with a single amino acid deletion (Delta E302/303) in the protein torsinA. TorsinA is an AAA+ ATPase in the endoplasmic reticulum, but what it does is unknown. Here, we use torsinA mutants with defects in ATP hydrolysis (E171Q, ATP-bound) and ATP binding (K108A, ATP-free) to probe torsinA's normal cellular function. Surprisingly, ATP-bound torsinA is recruited to the nuclear envelope (NE) of transfected cells, where it alters connections between inner and outer nuclear membranes. In contrast, ATP-free torsinA is diffusely distributed throughout the endoplasmic reticulum and has no effect on the NE. Among AAA+ ATPases, affinity for substrates is high in the ATP-bound and low in the ATP-free state, leading us to propose that component(s) of the NE may be substrates for torsinA. We also find that the disease-promoting Delta E302/303 mutant is in the NE, and that this relocalization, as well as the mutant's previously described ability to induce membranous inclusions, is eliminated by the K108A ATP-binding mutation. These results suggest that changes in interactions involving torsinA in the NE could be important for the pathogenesis of dystonia and point to torsinA and related proteins as a class of ATPases that may operate in the NE.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adenosine Triphosphatases / genetics
  • Adenosine Triphosphatases / metabolism*
  • Adenosine Triphosphate / metabolism
  • Amino Acid Motifs
  • Animals
  • CHO Cells
  • COS Cells
  • Conserved Sequence
  • Cricetinae
  • Dystonia Musculorum Deformans / metabolism*
  • Mutagens
  • Nuclear Envelope / metabolism*


  • Mutagens
  • Adenosine Triphosphate
  • Adenosine Triphosphatases