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

Zhu, Linghua; Wrabl, James O.; Hayashi, Adam; Rose, Lesilee S.; Thomas, Philip

doi:10.1091/mbc.e08-01-0015

Cited by 54 publications

(99 citation statements)

References 64 publications

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“…However, unlike the torsinA ⌬E mutation, the torsinA ⌬323-328 mutation does not affect the interaction of torsinA with printor. These data suggest that the printor binding site involves the second ␣-helix in the torsinA C-terminal region where glutamate residues 302 and 303 reside, but not the extreme ␣-helix in the torsinA C-terminal tail where amino acids Phe 323 -Tyr 328 reside (72). Thus, deletion of a single glutamate residue at positions 302 or 303 (torsinA ⌬E) would alter the helical register and disrupt the ability of torsinA to bind printor, whereas deletion of amino acids Phe 323 -Tyr 328 (torsinA ⌬323-328) would not affect the ability of torsinA to bind printor.…”

Section: Discussionmentioning

confidence: 89%

Printor, a Novel TorsinA-interacting Protein Implicated in Dystonia Pathogenesis

Giles

Chin

2009

Journal of Biological Chemistry

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Early onset generalized dystonia (DYT1) is an autosomal dominant neurological disorder caused by deletion of a single glutamate residue (torsinA ⌬E) in the C-terminal region of the AAA ؉ (ATPases associated with a variety of cellular activities) protein torsinA. The pathogenic mechanism by which torsinA ⌬E mutation leads to dystonia remains unknown. Here we report the identification and characterization of a 628-amino acid novel protein, printor, that interacts with torsinA. Printor co-distributes with torsinA in multiple brain regions and colocalizes with torsinA in the endoplasmic reticulum. Interestingly, printor selectively binds to the ATP-free form but not to the ATP-bound form of torsinA, supporting a role for printor as a cofactor rather than a substrate of torsinA. The interaction of printor with torsinA is completely abolished by the dystoniaassociated torsinA ⌬E mutation. Our findings suggest that printor is a new component of the DYT1 pathogenic pathway and provide a potential molecular target for therapeutic intervention in dystonia.Early onset generalized torsion dystonia (DYT1) is the most common and severe form of hereditary dystonia, a movement disorder characterized by involuntary movements and sustained muscle spasms (1). This autosomal dominant disease has childhood onset and its dystonic symptoms are thought to result from neuronal dysfunction rather than neurodegeneration (2, 3). Most DYT1 cases are caused by deletion of a single glutamate residue at positions 302 or 303 (torsinA ⌬E) of the 332-amino acid protein torsinA (4). In addition, a different torsinA mutation that deletes amino acids Phe 323 -Tyr 328(torsinA ⌬323-328) was identified in a single family with dystonia (5), although the pathogenic significance of this torsinA mutation is unclear because these patients contain a concomitant mutation in another dystonia-related protein, ⑀-sarcoglycan (6). Recently, genetic association studies have implicated polymorphisms in the torsinA gene as a genetic risk factor in the development of adult-onset idiopathic dystonia (7,8).TorsinA contains an N-terminal endoplasmic reticulum (ER) 3 signal sequence and a 20-amino acid hydrophobic region followed by a conserved AAA ϩ (ATPases associated with a variety of cellular activities) domain (9, 10). Because members of the AAA ϩ family are known to facilitate conformational changes in target proteins (11,12), it has been proposed that torsinA may function as a molecular chaperone (13,14). TorsinA is widely expressed in brain and multiple other tissues (15) and is primarily associated with the ER and nuclear envelope (NE) compartments in cells (16 -20). TorsinA is believed to mainly reside in the lumen of the ER and NE (17-19) and has been shown to bind lamina-associated polypeptide 1 (LAP1) (21), lumenal domain-like LAP1 (LULL1) (21), and nesprins (22). In addition, recent evidence indicates that a significant pool of torsinA exhibits a topology in which the AAA ϩ domain faces the cytoplasm (20). In support of this topology, torsinA is found in the...

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Section: Discussionmentioning

confidence: 89%

Printor, a Novel TorsinA-interacting Protein Implicated in Dystonia Pathogenesis

Giles

Chin

2009

Journal of Biological Chemistry

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“…These results are the first demonstration that TorA indeed assembles into the kind of oligomer expected of an AAAϩ protein and establish that LULL1 changes TorA targeting without affecting its fundamental structure. Our mutagenesis experiments indicate that an N-terminal hydrophobic sequence distinct from TorA's core AAAϩ domain (Kock et al, 2006;Zhu et al, 2008) is required for this retargeting (Figure 4). It is therefore attractive to hypothesize that interaction with LULL1 causes a conformational change involving this N-terminal domain, enhancing TorA's affinity for something within the NE.…”

Section: Discussionmentioning

confidence: 89%

“…These results suggest a molecular loss-of-function that may correlate with the previously described inability of ⌬GAG-TorA to rescue the lethality of TorA knockout in the mouse (Dang et al, 2005; and could ultimately contribute to the development of DYT1 dystonia. At a structural level, comparison of TorA's AAAϩ domain to that of ClpB or ClpA suggests that the ⌬GAG deletion falls in a position that could perturb a helix preceding an ATP-interacting loop known as the sensor-2 motif thereby leading to a loss-offunction (Kock et al, 2006;Zhu et al, 2008). The fact that TorA is now established to be an oligomeric enzyme ( Figure 3) supports the possibility that mixed oligomers containing wild-type and mutant subunits could turn a loss-of-function mutation into a dominantly inherited trait.…”

Section: Discussionmentioning

confidence: 99%

LULL1 Retargets TorsinA to the Nuclear Envelope Revealing an Activity That Is Impaired by theDYT1Dystonia Mutation

Heyden

Naismith

Snapp

et al. 2009

MBoC

115

162

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TorsinA (TorA) is an AAA؉ ATPase in the endoplasmic reticulum (ER) lumen that is mutated in early onset DYT1 dystonia. TorA is an essential protein in mice and is thought to function in the nuclear envelope (NE) despite localizing throughout the ER. Here, we report that transient interaction of TorA with the ER membrane protein LULL1 targets TorA to the NE. FRAP and Blue Native PAGE indicate that TorA is a stable, slowly diffusing oligomer in either the absence or presence of LULL1. Increasing LULL1 expression redistributes both wild-type and disease-mutant TorA to the NE, while decreasing LULL1 with shRNAs eliminates intrinsic enrichment of disease-mutant TorA in the NE. When concentrated in the NE, TorA displaces the nuclear membrane proteins Sun2, nesprin-2G, and nesprin-3 while leaving nuclear pores and Sun1 unchanged. Wild-type TorA also induces changes in NE membrane structure. Because SUN proteins interact with nesprins to connect nucleus and cytoskeleton, these effects suggest a new role for TorA in modulating complexes that traverse the NE. Importantly, once concentrated in the NE, disease-mutant TorA displaces Sun2 with reduced efficiency and does not change NE membrane structure. Together, our data suggest that LULL1 regulates the distribution and activity of TorA within the ER and NE lumen and reveal functional defects in the mutant protein responsible for DYT1 dystonia.

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“…Two other nucleotide interacting motifs, sensor I (XXXN 208 XX) and sensor II ( 318 GCK 320 ) motifs are also present ( Fig. 1, A and B) (28,29). Atypically, sensor II in torsinA does not contain the conserved arginine that interacts with the ␥-phosphate of ATP in other AAAϩ proteins.…”

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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

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

Cited by 54 publications

References 64 publications

Printor, a Novel TorsinA-interacting Protein Implicated in Dystonia Pathogenesis

Printor, a Novel TorsinA-interacting Protein Implicated in Dystonia Pathogenesis

LULL1 Retargets TorsinA to the Nuclear Envelope Revealing an Activity That Is Impaired by theDYT1Dystonia Mutation

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

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