Regulation of torsin ATPases by LAP1 and LULL1

Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06520-8114.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 04/2013; 110(17). DOI: 10.1073/pnas.1300676110
Source: PubMed


TorsinA is a membrane-associated AAA+ (ATPases associated with a variety of cellular activities) ATPase implicated in primary dystonia, an autosomal-dominant movement disorder. We reconstituted TorsinA and its cofactors in vitro and show that TorsinA does not display ATPase activity in isolation; ATP hydrolysis is induced upon association with LAP1 and LULL1, type II transmembrane proteins residing in the nuclear envelope and endoplasmic reticulum. This interaction requires TorsinA to be in the ATP-bound state, and can be attributed to the luminal domains of LAP1 and LULL1. This ATPase activator function controls the activities of other members of the Torsin family in distinct fashion, leading to an acceleration of the hydrolysis step by up to two orders of magnitude. The dystonia-causing mutant of TorsinA is defective in this activation mechanism, suggesting a loss-of-function mechanism for this congenital disorder.

Download full-text


Available from: Chenguang Zhao
  • Source
    • "As noted above, previous studies on purified full-length torsinA failed to detect oligomeric species, which could have been the result of detergent-induced destabilization of intersubunit contacts (Kustedjo et al. 2003). Other experiments using a purified protein detected higher molecular weight species that were not further resolved (Zhao et al. 2013). To obtain enriched soluble protein in the absence of a detergent, we produced a truncated torsinA variant lacking the hydrophobic membrane-binding region, torsinAΔ40 (Liu et al. 2003). "
    [Show abstract] [Hide abstract]
    ABSTRACT: A single GAG codon deletion in the gene encoding torsinA is linked to most cases of early-onset torsion dystonia. TorsinA is an ER-localized membrane-associated ATPase from the AAA+ superfamily with an unknown biological function. We investigated the formation of oligomeric complexes of torsinA in cultured mammalian cells and found that wild type torsinA associates into a complex with a molecular weight consistent with that of a homohexamer. Interestingly, the dystonia-linked variant torsinAΔE displayed a reduced propensity to form the oligomers compared to the wild type protein. We also discovered that the deletion of the N-terminal membrane-associating region of torsinA abolished oligomer formation. Our results demonstrate that the dystonia-linked mutation in the torsinA gene produces a protein variant that is deficient in maintaining its oligomeric state and suggest that ER membrane association is required to stabilize the torsinA complex.
    Full-text · Article · Dec 2014 · SpringerPlus
  • Source
    • "Abl2, encodes Arg, an F-actin-binding kinase that overlaps in function with Abl1, a related kinase with a critical role in lymphocyte development and signaling [49] [50]. Tor1aip1 (LAP11) and Tor1aip2 (LULL1), two neighboring genes, encode proteins which regulate the activity of Torsin A, an cytoplasmic ATPase [51] [52] that is linked to the nuclear skeleton, cell cycle, and lamins [53]. Axdnd1 (axonemal dynein light chain domain containing 1) encodes a microtubule-binding protein with a role in intracellular transport. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Sjogren’s syndrome (SS) is characterized by salivary gland leukocytic infiltrates and impaired salivation (xerostomia). Cox-2 (Ptgs2) is located on chromosome 1 within the span of the Aec2 region. In an attempt to demonstrate that COX-2 drives antibody-dependent hyposalivation, NOD.B10 congenic mice bearing a Cox-2flox gene were generated. A congenic line with non-NOD alleles in Cox-2-flanking genes failed manifest xerostomia. Further backcrossing yielded disease-susceptible NOD.B10 Cox-2flox lines; fine genetic mapping determined that critical Aec2 genes lie within a 1.56 to 2.17 Mb span of DNA downstream of Cox-2. Bioinformatics analysis revealed that susceptible and non-susceptible lines exhibit non-synonymous coding SNPs in 8 protein-encoding genes of this region, thereby better delineating candidate Aec2 alleles needed for SS xerostomia.
    Full-text · Article · Jul 2014 · Clinical Immunology
  • Source
    • "Subsequently, LAP1 has been implicated in the regulation of torsinA ATPase which is known to cause the severe movement disorder DYT1 dystonia (MIM 128100) [11] [12]. Another torsinA-interacting protein, 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 torsinA. "
    [Show abstract] [Hide abstract]
    ABSTRACT: 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.
    Full-text · Article · May 2014 · Neuromuscular Disorders
Show more