%0 Journal Article
%T The nuclear envelope localization of DYT1 dystonia torsinA-¦¤E requires the SUN1 LINC complex component
%A Michael T Jungwirth
%A Dhivya Kumar
%A Danielle Y Jeong
%A Rose E Goodchild
%J BMC Cell Biology
%D 2011
%I BioMed Central
%R 10.1186/1471-2121-12-24
%X We confirm that NE-localized torA-¦¤E does not co-immunoprecipitate with LAP1, and find that torA-¦¤E continues to concentrate in the NE of cells that lack LAP1. Instead, we find that variability in torA-¦¤E localization correlates with the presence of the SUN-domain and Nesprin proteins that assemble into the LINC complex. We also find that siRNA depletion of SUN1, but not other LINC complex components, removes torA-¦¤E from the NE. In contrast, the LAP1-dependent NE-accumulation of an ATP-locked torA mutant is unaffected by loss of LINC complex proteins. This SUN1 dependent torA-¦¤E localization requires the torA membrane association domain, as well as a putative substrate-interaction residue, Y147, neither of which are required for torA interaction with LAP1. We also find that mutation of these motifs, or depletion of SUN1, decreases the amount of torA-WT that colocalizes with NE markers, indicating that each also underlies a normal NE-localized torA binding interaction.These data suggest that the disease causing ¦¤E mutation promotes an association between torA and SUN1 that is distinct to the interaction between LAP1 and ATP-bound torA. This evidence for two NE-localized binding partners suggests that torA may act on multiple substrates and/or possesses regulatory co-factor partners. In addition, finding that the DYT1 mutation causes abnormal association with SUN1 implicates LINC complex dysfunction in DYT1 dystonia pathogenesis, and suggests a gain-of-function activity contributes to this dominantly inherited disease.DYT1 dystonia is a neurological disease characterized by prolonged, involuntary movements that develop in childhood or early adolescence, and occur in the absence of CNS pathology [1,2]. The disease is caused by an in-frame, loss-of-function mutation that removes a glutamic acid residue (¦¤E) from torA [3,4]. TorA is a member of the AAA+ ATPase family (ATPases Associated with a variety of cellular Activities) that typically couple the energy released by
%K torsinA
%K LINC complex
%K AAA+ protein
%K Nuclear Envelope
%K SUN1
%K DYT1 dystonia
%U http://www.biomedcentral.com/1471-2121/12/24