Printor, a novel torsinA-interacting protein implicated in dystonia pathogenesis.
Early onset generalized dystonia (DYT1) is an autosomal dominant neurological disorder caused by deletion of a single glutamate residue (torsinA DeltaE) in the C-terminal region of the AAA(+) (ATPases associated with a variety of cellular activities) protein torsinA. The pathogenic mechanism by which torsinA DeltaE mutation leads to dystonia remains unknown. Here we report the identification and characterization of a 628-amino acid novel protein, printor, that interacts with torsinA. Printor co-distributes with torsinA in multiple brain regions and co-localizes with torsinA in the endoplasmic reticulum. Interestingly, printor selectively binds to the ATP-free form but not to the ATP-bound form of torsinA, supporting a role for printor as a cofactor rather than a substrate of torsinA. The interaction of printor with torsinA is completely abolished by the dystonia-associated torsinA DeltaE mutation. Our findings suggest that printor is a new component of the DYT1 pathogenic pathway and provide a potential molecular target for therapeutic intervention in dystonia.
Giles
Lisa M
LM
Department of Pharmacology, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
Li
Lian
L
Chin
Lih-Shen
LS
D001921:Brain / Q000378:metabolism; D002352:Carrier Proteins / Q000096:biosynthesis / Q000502:physiology*; D002460:Cell Line; D045744:Cell Line, Tumor; D004421:Dystonia / Q000378:metabolism / Q000473:pathology*; D004721:Endoplasmic Reticulum / Q000378:metabolism; D005786:Gene Expression Regulation; D006031:Glycosylation; D006367:HeLa Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008954:Models, Biological; D018832:Molecular Chaperones / Q000737:chemistry*; D009154:Mutation; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D020798:Two-Hybrid System Techniques
D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; C543795:KLHL14 protein, human; D018832:Molecular Chaperones; C108175:TOR1A protein, human