The BiP Molecular Chaperone Plays Multiple Roles during the Biogenesis of TorsinA, an AAA+ ATPase Associated with the Neurological Disease Early-onset Torsion Dystonia

Zacchi, Lucía F.; Wu, Ho Sheng; Bell, Samantha L.; Millen, Linda; Paton, Adrienne W.; Paton, James C.; Thomas, Philip; Żółkiewski, Michał; Brodsky, Jeffrey L.

doi:10.1074/jbc.m113.529123

Cited by 25 publications

(61 citation statements)

References 163 publications

(190 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…As shown in Figure 3A, we pulled out both TorA-GFP and TorA-∆E-GFP alongside at least one major binding partner of ~70 kD, which we identified by mass spectrometry (MS) to be Kar2 (the orthologue of the ER chaperone, BiP). This result is consistent with previous work and suggests Kar2 plays a critical role in ensuring ER translocation and/or stability of these human proteins (Zacchi et al, 2014). It also remains formally possible that TorA forms a functional complex with Kar2 and contributes to protein quality control pathways in the ER.…”

Section: Tora and Tora-∆e Specifically Interact With Ne Proteinssupporting

confidence: 93%

“…Several prior studies have expressed TorA in budding yeast, but no clear functional insight for TorA has emerged (Valastyan and Lindquist, 2011;Zacchi et al, 2014;Adam et al, 2017;Zacchi et al, 2017). However, given that these studies were largely performed before the discovery of the LAP1 and LULL1 co-factors required for TorA ATPase activity, we felt it was worthwhile to revisit this system using the fully functional enzyme complex.…”

Section: Tora Accumulation At Spbs Requires Oligomerizationmentioning

confidence: 99%

See 1 more Smart Citation

Expression of TorsinA in a heterologous yeast system reveals interactions with conserved lumenal domains of LINC and nuclear pore complexes

Chalfant

Barber

Borah

et al. 2018

Preprint

View full text Add to dashboard Cite

DYT1 dystonia is caused by an in-frame deletion of a glutamic acid codon in the gene encoding the AAA+ ATPase TorsinA. TorsinA localizes within the lumen of the nuclear envelope/ER and binds to a membrane-spanning co-factor, LAP1 or LULL1, to form an ATPase; the substrate(s) of TorsinA remain ill defined. Here we use budding yeast, which lack Torsins, to interrogate TorsinA function. We show that TorsinA accumulates at nuclear envelope embedded spindle pole bodies (SPBs) in a way that requires its oligomerization and the conserved SUN-domain protein, Mps3. TorsinA is released from SPBs upon expression of LAP1 and stabilized by LAP1 mutants incapable of stimulating TorsinA ATPase activity, suggesting the recapitulation of a TorsinA-substrate cycle. While the expression of TorsinA or TorsinA-ΔE impacts the fitness of strains expressing mps3 alleles, a genetic interaction with a conserved component of the nuclear pore complex, Pom152, is specific for TorsinA. This specificity is mirrored by a physical interaction between Pom152 and TorsinA, but not TorsinA-ΔE. These data suggest that TorsinA-nucleoporin interactions would be abrogated by TorsinA-ΔE, providing new experimental avenues to interrogate the molecular basis behind nuclear envelope herniations seen in cells lacking TorsinA function.

show abstract

Section: Tora and Tora-∆e Specifically Interact With Ne Proteinssupporting

confidence: 93%

Section: Tora Accumulation At Spbs Requires Oligomerizationmentioning

confidence: 99%

Expression of TorsinA in a heterologous yeast system reveals interactions with conserved lumenal domains of LINC and nuclear pore complexes

Chalfant

Barber

Borah

et al. 2018

Preprint

View full text Add to dashboard Cite

show abstract

“…In a follow-up study, knockdown of wild-type TorsinA was also shown to increase the sensitivity of MEFs and cortical neurons to oxidative stress (Chen et al, 2010b). Of note, TorsinA ΔE has an increased dependence on the ER chaperone BiP for proper folding (Zacchi et al, 2014), suggesting that the disease-causing mutation affects Torsin folding and stability.…”

Section: Torsina: Disease Association and Mutant Phenotypes In Animalmentioning

confidence: 99%

Torsins: not your typical AAA+ ATPases

Rose

Brown

Schlieker

2015

Critical Reviews in Biochemistry and Molecular Biology

View full text Add to dashboard Cite

Torsin ATPases (Torsins) belong to the widespread AAA+ (ATPases associated with a variety of cellular activities) family of ATPases, which share structural similarity but have diverse cellular functions. Torsins are outliers in this family because they lack many characteristics of typical AAA+ proteins, and they are the only members of the AAA+ family located in the endoplasmic reticulum and contiguous perinuclear space. While it is clear that Torsins have essential roles in many, if not all metazoans, their precise cellular functions remain elusive. Studying Torsins has significant medical relevance since mutations in Torsins or Torsin-associated proteins result in a variety of congenital human disorders, the most frequent of which is Early Onset Torsion (DYT1) Dystonia, a severe movement disorder. A better understanding of the Torsin system is needed to define the molecular etiology of these diseases, potentially enabling corrective therapy. Here, we provide a comprehensive overview of the Torsin system in metazoans, discuss functional clues obtained from various model systems and organisms, and provide a phylogenetic and structural analysis of Torsins and their regulatory cofactors in relation to disease-causative mutations. Moreover, we review recent data that has led to a dramatically improved understanding of these machines at a molecular level, providing a foundation for investigating the molecular defects underlying the associated movement disorders. Lastly, we discuss our ideas on how recent progress may be utilized to inform future studies aimed at determining the cellular role(s) of these atypical molecular machines and their implications for dystonia treatment options.

show abstract

“…Yeast protein extracts were prepared for western blotting as previously described 47 . Samples resolved by SDS-PAGE were transferred to nitrocellulose membranes and blotted using the following antibodies: monoclonal mouse anti-HA (1:2000 dilution, ThermoFisher, 32–6700) and HRP-conjugated horse anti-mouse IgG (1:2000 dilution, Cell Signaling, 7076S).…”

Section: Methodsmentioning

confidence: 99%

N-glycosylation Triggers a Dual Selection Pressure in Eukaryotic Secretory Proteins

Medus

Gómez

Zacchi

et al. 2017

Sci Rep

Self Cite

View full text Add to dashboard Cite

Nearly one third of the eukaryotic proteome traverses the secretory pathway and most of these proteins are N-glycosylated in the lumen of the endoplasmic reticulum. N-glycans fulfill multiple structural and biological functions, and are crucial for productive folding of many glycoproteins. N-glycosylation involves the attachment of an oligosaccharide to selected asparagine residues in the sequence N-X-S/T (X ≠ P), a motif known as an N-glycosylation’sequon’. Mutations that create novel sequons can cause disease due to the destabilizing effect of a bulky N-glycan. Thus, an analogous process must have occurred during evolution, whenever ancestrally cytosolic proteins were recruited to the secretory pathway. Here, we show that during evolution N-glycosylation triggered a dual selection pressure on secretory pathway proteins: while sequons were positively selected in solvent exposed regions, they were almost completely eliminated from buried sites. This process is one of the sharpest evolutionary signatures of secretory pathway proteins, and was therefore critical for the evolution of an efficient secretory pathway.

show abstract

The BiP Molecular Chaperone Plays Multiple Roles during the Biogenesis of TorsinA, an AAA+ ATPase Associated with the Neurological Disease Early-onset Torsion Dystonia

Abstract: Background:The ⌬E mutation in the AAA ϩ ATPase torsinA is associated with the neurological disease torsion dystonia.

Cited by 25 publications

References 163 publications

Expression of TorsinA in a heterologous yeast system reveals interactions with conserved lumenal domains of LINC and nuclear pore complexes

Expression of TorsinA in a heterologous yeast system reveals interactions with conserved lumenal domains of LINC and nuclear pore complexes

Torsins: not your typical AAA+ ATPases

N-glycosylation Triggers a Dual Selection Pressure in Eukaryotic Secretory Proteins

Contact Info

Product

Resources

About