Interaction of TorsinA with Its Major Binding Partners Is Impaired by the Dystonia-associated ΔGAG Deletion

Naismith, Teresa V.; Dalal, Seema; Hanson, Phyllis I.

doi:10.1074/jbc.m109.020164

Cited by 90 publications

(122 citation statements)

References 43 publications

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“…3E), consistent with our previous data for LULL1 and TorB (24). All in all, these cross-linking experiments faithfully recapitulate the previously established nucleotide dependency of the cofactor interaction, as well as its disruption by the ΔE mutation (3,4,21). Notably, similar results were obtained when BPA was installed instead on the activator side of the interface for both LAP1 and LULL1 in the context of full-length TorA (Fig.…”

Section: Significancesupporting

confidence: 91%

“…We additionally engineered equivalent Torsin variants carrying the disease-causing singleglutamate deletion (ΔE302/E303 or ΔE). This mutation was previously shown to disrupt cofactor binding with a concomitant loss of ATPase activity (3,4,21). The Torsin-BPA/LAP1 complexes were partially purified in the presence of ATP by a single purification step.…”

Section: Significancementioning

confidence: 99%

“…To this end, we cotransfected TorA and the respective HA-tagged luminal domains and their mutant derivatives in 293T cells. We limited our analysis to HA-tagged variants of the luminal domains of LAP1/LULL1 and the hydrolysis-deficient TorA trap mutant TorA E171Q because LAP1 and LULL1 preferentially interact with TorA in its ATP-bound conformation and the luminal domains are necessary and sufficient for this interaction (3,4,21). Mild detergent extracts were prepared 24 h posttransfection and subjected to immunoprecipitation using anti-HA.…”

Section: Proposed Arginine Finger Residues In Lap1 and Lull1 Are Notmentioning

confidence: 99%

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The mechanism of Torsin ATPase activation

Brown

Zhao

Chase

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

146

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Torsins are membrane-associated ATPases whose activity is dependent on two activating cofactors, lamina-associated polypeptide 1 (LAP1) and luminal domain-like LAP1 (LULL1). The mechanism by which these cofactors regulate Torsin activity has so far remained elusive. In this study, we identify a conserved domain in these activators that is predicted to adopt a fold resembling an AAA+ (ATPase associated with a variety of cellular activities) domain. Within these domains, a strictly conserved Arg residue present in both activating cofactors, but notably missing in Torsins, aligns with a key catalytic Arg found in AAA+ proteins. We demonstrate that cofactors and Torsins associate to form heterooligomeric assemblies with a defined Torsin-activator interface. In this arrangement, the highly conserved Arg residue present in either cofactor comes into close proximity with the nucleotide bound in the neighboring Torsin subunit. Because this invariant Arg is strictly required to stimulate Torsin ATPase activity but is dispensable for Torsin binding, we propose that LAP1 and LULL1 regulate Torsin ATPase activity through an active site complementation mechanism.DYT1 dystonia | nuclear envelope | ATPase | Torsin T orsin ATPases belong to the AAA+ (ATPase associated with a variety of cellular activities) superfamily of ATPases (1) but are unusual in that they lack conserved catalytic residues that are typically found in related ATPases (2, 3). Accordingly, Torsins do not display ATPase activity unless they are engaged by their regulatory cofactors lamina-associated polypeptide 1 (LAP1) or luminal domain-like LAP1 (LULL1) (4), which are type II transmembrane proteins residing in the nuclear envelope and endoplasmic reticulum (ER) (5, 6). This property stands in sharp contrast to the behavior of closely related Clp/Hsp100 ATPases, which display considerable basal ATPase activities that are moderately stimulated by their substrates (7,8). Although a number of Clp/Hsp100 proteins use distinct cofactors that confer substrate specificity to the typically hexameric ATPase ring, they operate via similar principles (9). Substrates ultimately engage the pore at the center of the oligomeric assembly. This narrow annulus is defined by pore loops that emanate from each subunit and harbor a conserved aromatic residue that defines the center of the pore (10). The energy of ATP hydrolysis is invested in threading the substrate through this axial channel, and the substrate is unfolded in the process (11).Much less is known about the mode of action of Torsin ATPases, although it is clear that regulation of Torsin activity is of vital importance in an organismal context. A mutation in TorsinA (TorA) causing the movement disorder primary dystonia (12) renders TorA unresponsive to its binding partners LAP1 and LULL1 (4), and a homozygous "knock-in" of this disease allele in mice causes a lethal phenotype, as does a TorA KO (13). A conditional deletion of TorA from the CNS in mice accurately replicates the symptoms of primary dystonia (14). In add...

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Section: Significancesupporting

confidence: 91%

Section: Significancementioning

confidence: 99%

Section: Proposed Arginine Finger Residues In Lap1 and Lull1 Are Notmentioning

confidence: 99%

See 1 more Smart Citation

The mechanism of Torsin ATPase activation

Brown

Zhao

Chase

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

146

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“…TorsinA is diffusely distributed throughout the endoplasmic reticulum and the nuclear envelope continuity but some cell types exhibit a preference for the nuclear envelope [24,25]. Luminal domain-like LAP1 (LULL1) encoded by TOR1AIP2 is located in the endoplasmic reticulum and shares homologous C-terminal regions with LAP1 allowing interaction with ER-located torsinA [11,24].…”

Section: Discussionmentioning

confidence: 99%

“…It was suggested that LAP1 and LULL1 have similar modes of action on torsinA and that regulation of its ATPase activity is dependent on the dose of its cofactors [12]. Furthermore, distribution of torsinA might be regulated by the relative abundance of its binding partners in the ER and the nuclear envelope [24]. According to these hypotheses, overexpression of LULL1 observed in the patient IV:2 might have been associated with the absence of LAP1B and these two proteins might have a compensatory effect on each other.…”

Section: Discussionmentioning

confidence: 99%

Mutation in TOR1AIP1 encoding LAP1B in a form of muscular dystrophy: A novel gene related to nuclear envelopathies

Kayman-Kurekci

Talim

Korkusuz

et al. 2014

Neuromuscular Disorders

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We performed genome-wide homozygosity mapping and mapped a novel myopathic phenotype to chromosomal region 1q25 in a consanguineous family with three affected individuals manifesting proximal and distal weakness and atrophy, rigid spine and contractures of the proximal and distal interphalangeal hand joints. Additionally, cardiomyopathy and respiratory involvement were noted. DNA sequencing of torsinA-interacting protein 1 (TOR1AIP1) gene encoding lamina-associated polypeptide 1B (LAP1B), showed a homozygous c.186delG mutation that causes a frameshift resulting in a premature stop codon (p.E62fsTer25). We observed that expression of LAP1B was absent in the patient skeletal muscle fibres. Ultrastructural examination showed intact sarcomeric organization but alterations of the nuclear envelope including nuclear fragmentation, chromatin bleb formation and naked chromatin. LAP1B is a type-2 integral membrane protein localized in the inner nuclear membrane that binds to both A-and B-type lamins, and is involved in the regulation of torsinA ATPase. Interestingly, luminal domain-like LAP1 (LULL1)-an endoplasmic reticulum-localized partner of torsinA-was overexpressed in the patient's muscle in the absence of LAP1B. Therefore, the findings suggest that LAP1 and LULL1 might have a compensatory effect on each other. This study expands the spectrum of genes associated with nuclear envelopathies and highlights the critical function for LAP1B in striated muscle.

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Emerging Area: TorsinA, a Novel ATP‐Dependent Factor Linked to Dystonia

Żółkiewski

2011

Protein Chaperones and Protection From Neurodegenerative Diseases

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Interaction of TorsinA with Its Major Binding Partners Is Impaired by the Dystonia-associated ΔGAG Deletion

Abstract: Early onset (DYT1) torsion dystonia is a dominantly inherited movement disorder associated with a three-base pair (

Cited by 90 publications

References 43 publications

The mechanism of Torsin ATPase activation

The mechanism of Torsin ATPase activation

Mutation in TOR1AIP1 encoding LAP1B in a form of muscular dystrophy: A novel gene related to nuclear envelopathies

Emerging Area: TorsinA, a Novel ATP‐Dependent Factor Linked to Dystonia

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