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Vol. 19, Issue 8, 3599-3612, August 2008

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The Torsin-family AAA+ Protein OOC-5 Contains a Critical Disulfide Adjacent to Sensor-II That Couples Redox State to Nucleotide Binding

Li Zhu^*, James O. Wrabl, Adam P. Hayashi, Lesilee S. Rose, and Philip J. Thomas^*

*Departments of Physiology and Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390; and Section of Molecular and Cellular Biology, University of California, Davis, CA 95616

Submitted January 9, 2008; Revised May 29, 2008; Accepted June 4, 2008
Monitoring Editor: Jeffrey L. Brodsky

A subgroup of the AAA+ proteins that reside in the endoplasmic reticulum and the nuclear envelope including human torsinA, a protein mutated in hereditary dystonia, is called the torsin family of AAA+ proteins. A multiple-sequence alignment of this family with Hsp100 proteins of known structure reveals a conserved cysteine in the C-terminus of torsin proteins within the Sensor-II motif. A structural model predicts this cysteine to be a part of an intramolecular disulfide bond, suggesting that it may function as a redox sensor to regulate ATPase activity. In vitro experiments with OOC-5, a torsinA homolog from Caenorhabditis elegans, demonstrate that redox changes that reduce this disulfide bond affect the binding of ATP and ADP and cause an attendant local conformational change detected by limited proteolysis. Transgenic worms expressing an ooc-5 gene with cysteine-to-serine mutations that disrupt the disulfide bond have a very low embryo hatch rate compared with wild-type controls, indicating these two cysteines are essential for OOC-5 function. We propose that the Sensor-II in torsin family proteins is a redox-regulated sensor. This regulatory mechanism may be central to the function of OOC-5 and human torsinA.

Address correspondence to: Philip J. Thomas (Philip.Thomas{at}utsouthwestern.edu)

Abbreviations used: AAA, ATPases associated with cellular activities; CD, circular dichroism; DTNB, (5,5'-dithiobis-(2-nitrobenzoic acid); DTT, dithiothreitol; ER, endoplasmic reticulum; ESI, electrospray ionization; GSH, reduced glutathione; GSSG, oxidized glutathione; IAA, iodoacetate; IAM, iodoacetamide; LC, liquid chromatography; MS, mass spectrometry; NE, nuclear envelope; RRS, redox-regulated sensor; TCEP, tris(2-carboxyethyl) phosphine.

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