Crystal structure of the TLDc domain of oxidation resistance protein 2 from zebrafish

Blaise, Mickaël; Alsarraf, Husam M. A. B.; Wong, Jaslyn E. M. M.; Midtgaard, Søren Roi; Laroche, Fabrice; Schack, Lotte; Spaink, Herman P.; Stougaard, Jens; Thirup, Søren

doi:10.1002/prot.24050

Cited by 33 publications

(44 citation statements)

References 24 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The TLDc domain is coded by exons 19–24, which is indicated by a box in Figure . The TLDc domain is present in all eukaryotes and highly conserved among species (Blaise et al ., ). We compared the TLDc domain protein sequences of OXR1 among insects, nematode, mouse, human and yeast and found high similarity among the different species (Fig.…”

Section: Resultsmentioning

confidence: 97%

Oxidation resistance 1 (OXR1) participates in silkworm defense against bacterial infection through the JNK pathway

Su¹,

Zhang²,

2016

Insect Science

View full text Add to dashboard Cite

Bacterial infection causes enhanced reactive oxygen species (ROS) levels in insects. Oxidation resistance 1 (OXR1) plays an antioxidant role in eukaryotic organisms, including insects. In this report, we demonstrated that Pseudomonas aeruginosa and Staphylococcus aureus infection and hydrogen peroxide (H O ) injection induced the expression of specific transcriptional isoforms of OXR1 in larval silkworms. We further showed that a Jun kinase (JNK) pathway inhibitor, SP600125, down-regulated expression of OXR1 during infection, leading to elevated H O levels in the hemolymph, resulting in lower viability of the injected bacteria inside the silkworm larvae. Our study suggests that OXR1 participates in protecting larval silkworms from oxidative stress and bacterial infection through the JNK pathway.

show abstract

Section: Resultsmentioning

confidence: 97%

Oxidation resistance 1 (OXR1) participates in silkworm defense against bacterial infection through the JNK pathway

Su¹,

Zhang²,

2016

Insect Science

View full text Add to dashboard Cite

show abstract

“…The gene is expressed as several isoforms, all containing a C-terminal TLDc domain, which is highly conserved among species and present in all eukaryotes (Fig. 1 A) ( 53 , 54 ). The TLDc domain has also been shown to prevent oxidative damage in various organisms ( 51 , 52 , 55 ); however, its mechanism of action remains unclear.…”

Section: Resultsmentioning

confidence: 99%

“…Using our unbiased proteomic approach, we have demonstrated for the first time that Oxr1 binds to proteins involved in the oxidative stress response. This is significant as it has been shown that Oxr1 plays an important role in these pathways, although the molecular mechanisms are unclear; particularly as the three-dimensional structure of the highly conserved TLDc domain did not reveal similarity to known antioxidant proteins ( 53 ). Thus, we investigated binding partners of both the longest (Oxr1-FL) and the shortest (Oxr1-C) TLDc-containing isoforms of Oxr1 for a comprehensive study.…”

Section: Discussionmentioning

confidence: 99%

Oxr1 improves pathogenic cellular features of ALS-associated FUS and TDP-43 mutations

Finelli

Liu

et al. 2015

Human Molecular Genetics

View full text Add to dashboard Cite

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the loss of motor neuron-like cells. Mutations in the RNA- and DNA-binding proteins, fused in sarcoma (FUS) and transactive response DNA-binding protein 43 kDa (TDP-43), are responsible for 5–10% of familial and 1% of sporadic ALS cases. Importantly, aggregation of misfolded FUS or TDP-43 is also characteristic of several neurodegenerative disorders in addition to ALS, including frontotemporal lobar degeneration. Moreover, splicing deregulation of FUS and TDP-43 target genes as well as mitochondrial abnormalities are associated with disease-causing FUS and TDP-43 mutants. While progress has been made to understand the functions of these proteins, the exact mechanisms by which FUS and TDP-43 cause ALS remain unknown. Recently, we discovered that, in addition to being up-regulated in spinal cords of ALS patients, the novel protein oxidative resistance 1 (Oxr1) protects neurons from oxidative stress-induced apoptosis. To further understand the function of Oxr1, we present here the first interaction study of the protein. We show that Oxr1 binds to Fus and Tdp-43 and that certain ALS-associated mutations in Fus and Tdp-43 affect their Oxr1-binding properties. We further demonstrate that increasing Oxr1 levels in cells expressing specific Fus and Tdp-43 mutants improves the three main cellular features associated with ALS: cytoplasmic mis-localization and aggregation, splicing changes of a mitochondrial gene and mitochondrial defects. Taken together, these findings suggest that OXR1 may have therapeutic benefits for the treatment of ALS and related neurodegenerative disorders with TDP-43 pathology.

show abstract

“…We generated the structural model of human TBC1D24 with Phyre2, an online software, 21 based on the crystal structures of the TBC domain of TBC1D1 and TBC1D4 and the TBC, LysM, Domain catalytic (TLDc) domain of the zebrafish Oxr2 protein 22 . We made the three-dimentional figure using Pymol (version 1.6).…”

Section: Methodsmentioning

confidence: 99%

The genetic basis of DOORS syndrome: an exome-sequencing study

Campeau

Kasperavičiūtė²,

et al. 2014

The Lancet Neurology

144

View full text Add to dashboard Cite

SummaryBackgroundDeafness, onychodystrophy, osteodystrophy, mental retardation, and seizures (DOORS) syndrome is a rare autosomal recessive disorder of unknown cause. We aimed to identify the genetic basis of this syndrome by sequencing most coding exons in affected individuals.MethodsThrough a search of available case studies and communication with collaborators, we identified families that included at least one individual with at least three of the five main features of the DOORS syndrome: deafness, onychodystrophy, osteodystrophy, intellectual disability, and seizures. Participants were recruited from 26 centres in 17 countries. Families described in this study were enrolled between Dec 1, 2010, and March 1, 2013. Collaborating physicians enrolling participants obtained clinical information and DNA samples from the affected child and both parents if possible. We did whole-exome sequencing in affected individuals as they were enrolled, until we identified a candidate gene, and Sanger sequencing to confirm mutations. We did expression studies in human fibroblasts from one individual by real-time PCR and western blot analysis, and in mouse tissues by immunohistochemistry and real-time PCR.Findings26 families were included in the study. We did exome sequencing in the first 17 enrolled families; we screened for TBC1D24 by Sanger sequencing in subsequent families. We identified TBC1D24 mutations in 11 individuals from nine families (by exome sequencing in seven families, and Sanger sequencing in two families). 18 families had individuals with all five main features of DOORS syndrome, and TBC1D24 mutations were identified in half of these families. The seizure types in individuals with TBC1D24 mutations included generalised tonic-clonic, complex partial, focal clonic, and infantile spasms. Of the 18 individuals with DOORS syndrome from 17 families without TBC1D24 mutations, eight did not have seizures and three did not have deafness. In expression studies, some mutations abrogated TBC1D24 mRNA stability. We also detected Tbc1d24 expression in mouse phalangeal chondrocytes and calvaria, which suggests a role of TBC1D24 in skeletogenesis.InterpretationOur findings suggest that mutations in TBC1D24 seem to be an important cause of DOORS syndrome and can cause diverse phenotypes. Thus, individuals with DOORS syndrome without deafness and seizures but with the other features should still be screened for TBC1D24 mutations. More information is needed to understand the cellular roles of TBC1D24 and identify the genes responsible for DOORS phenotypes in individuals who do not have a mutation in TBC1D24.FundingUS National Institutes of Health, the CIHR (Canada), the NIHR (UK), the Wellcome Trust, the Henry Smith Charity, and Action Medical Research.

show abstract

Crystal structure of the TLDc domain of oxidation resistance protein 2 from zebrafish

Cited by 33 publications

References 24 publications

Oxidation resistance 1 (OXR1) participates in silkworm defense against bacterial infection through the JNK pathway

Oxidation resistance 1 (OXR1) participates in silkworm defense against bacterial infection through the JNK pathway

Oxr1 improves pathogenic cellular features of ALS-associated FUS and TDP-43 mutations

The genetic basis of DOORS syndrome: an exome-sequencing study

Contact Info

Product

Resources

About