A molecular mechanism underlying the neural-specific defect in torsinA mutant mice

Kim, Connie E.; Perez, Alex; Perkins, Guy; Ellisman, Mark H.; Dauer, William T.

doi:10.1073/pnas.0912877107

Cited by 143 publications

(230 citation statements)

References 20 publications

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“…Constitutive knockout of LAP1 in mice causes perinatal lethality; however, a very recent study reported that the conditional deletion of LAP1 from mouse striated muscle leads to muscular dystrophy whereas LAP1 deletion from hepatocytes does not affect liver function [13,26]. This model supports the notion that LAP1B has a specific role in striated muscle and represents a functional validation of the effect of LAP1B deficiency in human striated muscle.…”

Section: Discussionsupporting

confidence: 59%

“…Although knockdown of LAP1 or LULL1 does not seem to affect expression or localization of torsinA, mice lacking LAP1 exhibit perinatal lethality and LAP1 deficiency causes nuclear membrane abnormalities similar to those observed in torsinA-null cells [13,27]. On the other hand, overexpression of LAP1 and LULL1 recruits torsinA to the nuclear envelope [11,28].…”

Section: Discussionmentioning

confidence: 91%

“…These two proteins appear to have arisen from a gene duplication [11]. LAP1B is widely expressed in a variety of tissues, including skeletal muscle [11,13]. To date LAP1B has not been reported to be involved in any disease.…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Discussionsupporting

confidence: 59%

Section: Discussionmentioning

confidence: 91%

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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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“…A conditional deletion of TorA from the CNS in mice accurately replicates the symptoms of primary dystonia (14). In addition, LAP1-deficient mice display early perinatal lethality (15), again corroborating the physiological significance of regulation and dysregulation of Torsin activity.…”

mentioning

confidence: 64%

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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“…Although studied extensively, the function of LAP1 remains unclear. A recent report utilizing torsinA mutant mice showed that LAP1 and torsinA act in the same biological pathway required for normal nuclear membrane morphology in both neuronal and non-neuronal cells (44). The C-terminal lumenal domain of LAP1B is highly conserved, but its function is unknown; the N-terminal nucleoplasmic domain and the transmembrane span of LAP1B are necessary and sufficient for the nuclear localization of the molecule (45).…”

Section: Discussionmentioning

confidence: 99%

A Unique Redox-sensing Sensor II Motif in TorsinA Plays a Critical Role in Nucleotide and Partner Binding

Zhu

Millen

Mendoza

et al. 2010

Journal of Biological Chemistry

113

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Early onset dystonia is commonly associated with the deletion of one of a pair of glutamate residues (⌬E302/303) 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, ⌬E, 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, ⌬E, 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 cysteinecontaining 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.Torsion dystonia is an autosomal dominant movement disorder that causes the muscles to contract and spasm involuntarily. These muscle contractions force the body into repetitive movements and often twisted postures. The most common and severe early onset form of dystonia has been linked to the mutations in the human DYT1 (TOR1A) gene encoding the protein torsinA (1, 2). Although the function of torsinA and the mechanism underlying dystonia disease remain obscure, the sequence of torsinA is homologous to a large and diverse group of ATP-dependent oligomeric proteins named the AAAϩ protein family. The AAAϩ proteins typically form oligomeric rings that catalyze a variety of cellular processes, including protein translocation, membrane trafficking, and conformational remodeling of regulatory factors (3-5). TorsinA is the founding member of a subfamily of AAAϩ proteins that includes torsinB (TOR1B) and two other related gene products (TOR2A and TOR3A) in mammals and OOC-5 in Caenorhabditis elegans (1, 6, 7).The signal sequence and the following hydrophobic region at the N terminus (Fig. 1A) target torsinA to the lumen of the endoplasmic reticulum (ER). 3 In the ER, torsinA perhaps acts on secreted (8, 9) or stress-related protein substrates (10). Unlike ClpA and ClpB, torsinA lacks a substrate-binding domain or other functional region outside its ATPase domain (11). Experimental evidence suggests that torsinA mediates varied cellular activities, including protection from toxic cellular stress (12-15), trafficking of membrane-associated proteins (16), and synaptic vesicle recycling (17). In this regard, torsinA regulates trafficking of a G-protein-coupled recept...

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A molecular mechanism underlying the neural-specific defect in torsinA mutant mice

Cited by 143 publications

References 20 publications

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

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

The mechanism of Torsin ATPase activation

A Unique Redox-sensing Sensor II Motif in TorsinA Plays a Critical Role in Nucleotide and Partner Binding

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