A unique redox-sensing sensor II motif in TorsinA plays a critical role in nucleotide and partner binding.

Abstract

Early onset dystonia is commonly associated with the deletion of one of a pair of glutamate residues (ΔE302/303) near the C terminus of torsinA, a member of the AAA+ protein family (ATPases associated with a variety of cellular activities) located in the endoplasmic reticulum lumen. The functional consequences of the disease-causing mutation, ΔE, are not currently understood. By contrast to other AAA+ proteins, torsin proteins contain two conserved cysteine residues in the C-terminal domain, one of which is located in the nucleotide sensor II motif. Depending on redox status, an ATP hydrolysis mutant of torsinA interacts with lamina-associated polypeptide 1 (LAP1) and lumenal domain like LAP1 (LULL1). Substitution of the cysteine in sensor II diminishes the redox-regulated interaction of torsinA with these substrates. Significantly, the dystonia-causing mutation, ΔE, alters the ability of torsinA to mediate the redox-regulated interactions with LAP1 and LULL1. Limited proteolysis experiments reveal redox- and mutation-dependent changes in the local conformation of torsinA as a function of nucleotide binding. These results indicate that the cysteine-containing sensor II plays a critical role in redox sensing and the nucleotide and partner binding functions of torsinA and suggest that loss of this function of torsinA contributes to the development of DYT1 dystonia.

• Authors: Li Zhu, Linda Millen, Juan L Mendoza, Philip J Thomas
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 285 Issue 48 Pg. 37271-80 (Nov 26 2010) ISSN: 1083-351X [Electronic] United States
• PMID: 20861018 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Carrier Proteins
• HSC70 Heat-Shock Proteins
• HSPA8 protein, human
• Membrane Proteins
• Molecular Chaperones
• TOR1A protein, human
• TOR1AIP2 protein, human
• Adenosine Triphosphate

Topics

• Adenosine Triphosphate (metabolism)
• Amino Acid Motifs
• Animals
• COS Cells
• Carrier Proteins (genetics, metabolism)
• Chlorocebus aethiops
• Dystonia (genetics, metabolism)
• HSC70 Heat-Shock Proteins (genetics, metabolism)
• HeLa Cells
• Humans
• Membrane Proteins (genetics, metabolism)
• Molecular Chaperones (chemistry, genetics, metabolism)
• Mutation
• Oxidation-Reduction
• Protein Binding
• Protein Conformation