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, Philip J. Thomas

Research output: Contribution to journalArticle

42 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)3599-3612
Number of pages14
JournalMolecular Biology of the Cell
Volume19
Issue number8
DOIs
StatePublished - Aug 2008

Fingerprint

Disulfides
Oxidation-Reduction
Nucleotides
Cysteine
Proteins
Dystonic Disorders
Sequence Alignment
Structural Models
Nuclear Envelope
Caenorhabditis elegans
Endoplasmic Reticulum
Adenosine Diphosphate
Serine
Proteolysis
Adenosine Triphosphatases
Embryonic Structures
Adenosine Triphosphate
Mutation
Genes

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

The torsin-family AAA+ protein OOC-5 contains a critical disulfide adjacent to sensor-II that couples redox state to nucleotide binding. / Zhu, Li; Wrabl, James O.; Hayashi, Adam P.; Rose, Lesilee S.; Thomas, Philip J.

In: Molecular Biology of the Cell, Vol. 19, No. 8, 08.2008, p. 3599-3612.

Research output: Contribution to journalArticle

Zhu, Li ; Wrabl, James O. ; Hayashi, Adam P. ; Rose, Lesilee S. ; Thomas, Philip J. / The torsin-family AAA+ protein OOC-5 contains a critical disulfide adjacent to sensor-II that couples redox state to nucleotide binding. In: Molecular Biology of the Cell. 2008 ; Vol. 19, No. 8. pp. 3599-3612.
@article{3a67858734364208b33d37e6ab9abf0c,
title = "The torsin-family AAA+ protein OOC-5 contains a critical disulfide adjacent to sensor-II that couples redox state to nucleotide binding",
abstract = "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.",
author = "Li Zhu and Wrabl, {James O.} and Hayashi, {Adam P.} and Rose, {Lesilee S.} and Thomas, {Philip J.}",
year = "2008",
month = "8",
doi = "10.1091/mbc.E08-01-0015",
language = "English (US)",
volume = "19",
pages = "3599--3612",
journal = "Molecular Biology of the Cell",
issn = "1059-1524",
publisher = "American Society for Cell Biology",
number = "8",

}

TY - JOUR

T1 - The torsin-family AAA+ protein OOC-5 contains a critical disulfide adjacent to sensor-II that couples redox state to nucleotide binding

AU - Zhu, Li

AU - Wrabl, James O.

AU - Hayashi, Adam P.

AU - Rose, Lesilee S.

AU - Thomas, Philip J.

PY - 2008/8

Y1 - 2008/8

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=54249121433&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=54249121433&partnerID=8YFLogxK

U2 - 10.1091/mbc.E08-01-0015

DO - 10.1091/mbc.E08-01-0015

M3 - Article

C2 - 18550799

AN - SCOPUS:54249121433

VL - 19

SP - 3599

EP - 3612

JO - Molecular Biology of the Cell

JF - Molecular Biology of the Cell

SN - 1059-1524

IS - 8

ER -