scholarly journals Cryo-EM structure of human Nup155 reveals the biochemical basis for atrial fibrillation linked genetic mutation R391H

2021 ◽  
Author(s):  
Sangeeta Niranjan ◽  
Jyotsana Singh ◽  
Radha Chauhan
Keyword(s):  
Atrial Fibrillation ◽  
Sudden Cardiac Arrest ◽  
Genetic Mutation ◽  
Human Diseases ◽  
Nuclear Pore ◽  
List Type ◽  
Biochemical Basis ◽  
Cytoplasmic Transport ◽  
Middle Domain ◽  
N Terminus

SummaryHuman nuclear pore complexes are composed of ∼32 distinct nucleoporins to facilitate bidirectional nucleo-cytoplasmic transport. Many of them have been associated with various human diseases such as an inherited mutation (R391H) in Nup155 is shown as the clinical cause of atrial fibrillation and sudden cardiac arrest. Due to the lack of structural knowledge and mechanistic insights, the roles of Nups in NPC assembly and relevance in human diseases are very restricted. Here, we show the cryo-EM structure of human Nup155 at 5.2-5.7. Å resolution deciphered from 3 distinct particle classes: N-terminus (19-863), C-terminus (864-1337), and longer N-terminus (19-1069). It revealed intrinsic plasticity at the middle domain of Nup155 and the role of species-specific loop regions in an atypical 7-bladed β-propeller domain to provide a distinct interface for Nup93 and Nup35. Due to the proximity of these Nups interacting sites near the Arginine-391 position, atrial fibrillation linked genetic mutation (R391H) causes dissociation from NPC in absence of N-terminal 112 residues.HighlightsCryo-EM structure of human Nup155 at 5.2 Å resolutionSeven bladed β-propeller domain at N-terminus of Nup155 exhibited distinct features for interaction with Nup35 and Nup93The middle domain of Nup155 is highly dynamic in natureStructural mapping allows mechanistic interpretation of AF linked R391H mutation

PT365 Is there a biochemical basis for differential thromboembolic risk in atrial fibrillation? Studies with platelet nitric oxide signalling

Global Heart ◽  
2014 ◽  
Vol 9 (1) ◽  
pp. e240-e241
Author(s):  
Nathan E.K. Procter ◽  
Jocasta Ball ◽  
Doan Ngo ◽  
Yuliy Y. Chirkov ◽  
Jeffrey S. Isenberg ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Atrial Fibrillation ◽  
Biochemical Basis ◽  
Thromboembolic Risk

scholarly journals The Torsin/ NEP1R1-CTDNEP1/ Lipin axis regulates nuclear envelope lipid metabolism for nuclear pore complex insertion

2020 ◽  
Author(s):  
Julie Jacquemyn ◽  
Joyce Foroozandeh ◽  
Katlijn Vints ◽  
Jef Swerts ◽  
Patrik Verstreken ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Nuclear Envelope ◽  
Nuclear Pore Complex ◽  
Lipid Droplets ◽  
Nuclear Pore ◽  
List Type ◽  
Unknown Mechanism ◽  
Structure Lipid ◽  
Cellular Events ◽  
Upstream Regulator

AbstractTorsin ATPases of the endoplasmic reticulum (ER) and nuclear envelope (NE) lumen inhibit Lipin-mediated phosphatidate (PA) to diacylglycerol (DAG) conversion by an unknown mechanism. This excess PA metabolism is implicated in TOR1A/TorsinA diseases, but it is unclear whether it explains why Torsin concomitantly affects nuclear structure, lipid droplets (LD), organelle and cell growth. Here a fly miniscreen identified that Torsins affect these events via the NEP1R1-CTDNEP1 phosphatase complex. Further, Torsin homo-oligomerization rather than ATPase activity was key to function. NEP1R1-CTDNEP1 activates Lipin by dephosphorylation. We show that Torsin prevents CTDNEP1 from accumulating in the NE and excludes Lipin from the nucleus. Moreover, this repression of nuclear PA metabolism is required for interphase nuclear pore biogenesis. We conclude that Torsin is an upstream regulator of the NEP1R1-CTDNEP1/ Lipin pathway. This connects the ER/NE lumen with PA metabolism, and affects numerous cellular events including it has a previously unrecognized role in nuclear pore biogenesis.HighlightsNuclear envelope PA-DAG-TAG synthesis is independently regulated by Torsin and Torip/LAP1Torsin removes CTDNEP1 from the nuclear envelope and excludes Lipin from the nucleusExcess nuclear envelope NEP1R1-CTDNEP1/ Lipin activity impairs multiple aspects of NPC biogenesisNEP1R1-CTDNEP1/ Lipin inhibition prevents cellular defects associated with TOR1A and TOR1AIP1 / LAP1 disease

scholarly journals Thromboembolic complications of thyroid storm

2014 ◽  
Vol 2014 ◽  
Author(s):  
T Min ◽  
S Benjamin ◽  
L Cozma
Keyword(s):  
Atrial Fibrillation ◽  
Early Recognition ◽  
Massive Pulmonary Embolism ◽  
Clinical Findings ◽  
Favourable Outcome ◽  
Thyroid Storm ◽  
List Type ◽  
Chads2 Score ◽  
Prompt Treatment ◽  
Life Threatening

Summary Thyroid storm is a rare but potentially life-threatening complication of hyperthyroidism. Early recognition and prompt treatment are essential. Atrial fibrillation can occur in up to 40% of patients with thyroid storm. Studies have shown that hyperthyroidism increases the risk of thromboembolic events. There is no consensus with regard to the initiation of anticoagulation for atrial fibrillation in severe thyrotoxicosis. Anticoagulation is not routinely initiated if the risk is low on a CHADS2 score; however, this should be considered in patients with thyroid storm or severe thyrotoxicosis with impending storm irrespective of the CHADS2 risk, as it appears to increase the risk of thromboembolic episodes. Herein, we describe a case of thyroid storm complicated by massive pulmonary embolism. Learning points Diagnosis of thyroid storm is based on clinical findings. Early recognition and prompt treatment could lead to a favourable outcome. Hypercoagulable state is a recognised complication of thyrotoxicosis. Atrial fibrillation is strongly associated with hyperthyroidism and thyroid storm. Anticoagulation should be considered for patients with severe thyrotoxicosis and atrial fibrillation irrespective of the CHADS2 score. Patients with severe thyrotoxicosis and clinical evidence of thrombosis should be immediately anticoagulated until hyperthyroidism is under control.

scholarly journals Nuclear Targeting of Adenovirus Type 2 Requires CRM1-mediated Nuclear Export

2005 ◽  
Vol 16 (6) ◽  
pp. 2999-3009 ◽  
Author(s):  
Sten Strunze ◽  
Lloyd C. Trotman ◽  
Karin Boucke ◽  
Urs F. Greber
Keyword(s):  
Nuclear Export ◽  
Adenovirus Type ◽  
Nuclear Pore ◽  
Nuclear Targeting ◽  
Microtubule Organizing Center ◽  
Cytoplasmic Transport ◽  
Viral Particles ◽  
Organizing Center ◽  
Adenovirus Type 2

Incoming adenovirus type 2 (Ad2) and Ad5 shuttle bidirectionally along microtubules, biased to the microtubule-organizing center by the dynein/dynactin motor complex. It is unknown how the particles reach the nuclear pore complex, where capsids disassemble and viral DNA enters the nucleus. Here, we identified a novel link between nuclear export and microtubule-mediated transport. Two distinct inhibitors of the nuclear export factor CRM1, leptomycin B (LMB) and ratjadone A (RJA) or CRM1-siRNAs blocked adenovirus infection, arrested cytoplasmic transport of viral particles at the microtubule-organizing center or in the cytoplasm and prevented capsid disassembly and nuclear import of the viral genome. In mitotic cells where CRM1 is in the cytoplasm, adenovirus particles were not associated with microtubules but upon LMB treatment, they enriched at the spindle poles implying that CRM1 inhibited microtubule association of adenovirus. We propose that CRM1, a nuclear factor exported by CRM1 or a protein complex containing CRM1 is part of a sensor mechanism triggering the unloading of the incoming adenovirus particles from microtubules proximal to the nucleus of interphase cells.

68-year-old woman with paroxysmal atrial fibrillation

Heart ◽  
2018 ◽  
pp. heartjnl-2018-314143
Author(s):  
Eftihia Sbarouni ◽  
Nektarios Kogerakis ◽  
George Stavridis
Keyword(s):  
Atrial Fibrillation ◽  
Paroxysmal Atrial Fibrillation ◽  
Mitral Stenosis ◽  
Left Atrial ◽  
Septal Defect ◽  
Left Atrial Appendage ◽  
Atrial Myxoma ◽  
List Type ◽  
Left Atrial Myxoma ◽  
Left Atrial Appendage Aneurysm

QuestionWhat is the most likely diagnosis?Mitral stenosis.Pericardial cyst.Left atrial appendage aneurysm.Left atrial myxoma.Atrial septal defect.

scholarly journals Baculovirus Infection of Nondividing Mammalian Cells: Mechanisms of Entry and Nuclear Transport of Capsids

2001 ◽  
Vol 75 (2) ◽  
pp. 961-970 ◽  
Author(s):  
Nico-Dirk van Loo ◽  
Elisabetta Fortunati ◽  
Erich Ehlert ◽  
Martijn Rabelink ◽  
Frank Grosveld ◽  
...  
Keyword(s):  
Mammalian Cells ◽  
Fluorescent Protein ◽  
Nuclear Transport ◽  
Microscopic Analysis ◽  
Cell Types ◽  
Nuclear Pore ◽  
Fusion Event ◽  
Electron Microscopic ◽  
Cytoplasmic Transport ◽  
Baculovirus Infection

ABSTRACT We have studied the infection pathway of Autographa californica multinuclear polyhedrosis virus (baculovirus) in mammalian cells. By titration with a baculovirus containing a green fluorescent protein cassette, we found that several, but not all, mammalian cell types can be infected efficiently. In contrast to previous suggestions, our data show that the asialoglycoprotein receptor is not required for efficient infection. We demonstrate for the first time that this baculovirus can infect nondividing mammalian cells, which implies that the baculovirus is able to transport its genome across the nuclear membrane of mammalian cells. Our data further show that the virus enters via endocytosis, followed by an acid-induced fusion event, which releases the nucleocapsid into the cytoplasm. Cytochalasin D strongly reduces the infection efficiency but not the delivery of nucleocapsids to the cytoplasm, suggesting involvement of actin filaments in cytoplasmic transport of the capsids. Electron microscopic analysis shows the cigar-shaped nucleocapsids located at nuclear pores of nondividing cells. Under these conditions, we observed the viral genome, major capsid protein, and electron-dense capsids inside the nucleus. This suggests that the nucleocapsid is transported through the nuclear pore. This mode of transport seems different from viruses with large spherical capsids, such as herpes simplex virus and adenovirus, which are disassembled before nuclear transport of the genome. The implications for the application of baculovirus or its capsid proteins in gene therapy are discussed.

P38 Clinical pearl: pharmaceutical management of primary erythromelalgia (pe) (scn9a)

2018 ◽  
Vol 103 (2) ◽  
pp. e2.42-e2
Author(s):  
William Batten
Keyword(s):  
Pain Relief ◽  
Sodium Channel ◽  
Genetic Mutation ◽  
Lower Limbs ◽  
Therapeutic Drug ◽  
List Type ◽  
Voltage Gated Sodium Channel ◽  
Voltage Gated ◽  
Primary Erythromelalgia ◽  
At Home

SituationPatient RL is a 7 year old female with a confirmed genetic diagnosis for Primary Erythromelalgia PE, with a heterozygous sequence change in the SCN9A gene: c.2623C>G, p.(Gln875Glu). This genetic mutation of SCN9A results in sodium chanellopathy specifically for the voltage gated sodium channel Nav1.7. This genetic mutation makes the Nav1.7 channel hypersensitive to stimulus and over activation.1 As a result, she suffers from severe intermittent episodes of bilateral erythema and burning pain of the lower limbs. These symptoms are difficult to manage and PE is also known as ‘man-on-fire syndrome’.1BackgroundPE in a child is a complex diagnosis with severely limited pharmacological treatments available. Inadequate pain relief was achieved with routine analgesics such as paracetamol and ibuprofen. A multidisciplinary team (MDT) approach including pharmacy was implemented with; review of available literature, alternative medications for relief of pain and other PE symptoms, advice on formulation and dosing.OutcomeWhen initially diagnosed, RL was frequently admitted to hospital for uncontrollable and pain and the family were unable to manage at home. Since her diagnosis and full MDT involvement, her pain relief has improved, her hospital admissions have decreased and her family are coping better at home. However, despite pharmacological interventions she is still not entirely free from pain and her other symptoms. Patient RL has also received intensive psychology input for coping strategies in managing her pain, and her parents have received psychological and social input to help them. She is managing to walk more and but still relies on her pushchair. Her current medication regimen is as follows: gabapentin, cetirizine, chlorphenamine, naproxen, paracetamol, clonidine, mexiletine, amitriptyline and topical application of amitriptyline and ketamine. Unsuccessful treatments included: magnesium supplementation, menthol in aqueous cream, lidocaine patches, tramadol and aspirin.Lessons learntThere is little information in the literature on the treatment of paediatric patients with PE and they are mainly case reports. Management of RL has been multidisciplinary with pharmacy playing an important role advising on treatment of anecdotal evidence, dosing and formulation advice, counselling, sourcing amitriptyline and ketamine gel and therapeutic drug monitoring for mexiletine. Future treatments we hope to trial include novel drugs still in development that specifically target the voltage gated sodium channel Nav1.7 such as raxatrigine.ReferenceLawrence J. Nav1.7: A new channel for pain treatment. The Pharmaceutical Journal2016;296:7887. Available from: http://www.pharmaceutical-journal.com/publications/the-pharmaceutical-journal/20200841.article [Accessed: 26 July 2016.

scholarly journals Mutation in Nuclear Pore Component NUP155 Leads to Atrial Fibrillation and Early Sudden Cardiac Death

Cell ◽  
2008 ◽  
Vol 135 (6) ◽  
pp. 1017-1027 ◽  
Author(s):  
Xianqin Zhang ◽  
Shenghan Chen ◽  
Shin Yoo ◽  
Susmita Chakrabarti ◽  
Teng Zhang ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Sudden Cardiac Death ◽  
Cardiac Death ◽  
Nuclear Pore

scholarly journals The Nonstructural Proteins 3 and 5 from Flavivirus Modulate Nuclear-Cytoplasmic Transport and Innate Immune Response Targeting Nuclear Proteins

2018 ◽  
Author(s):  
Margot Cervantes-Salazar ◽  
Ana L. Gutiérrez-Escolano ◽  
José M. Reyes-Ruiz ◽  
Rosa M. del Angel
Keyword(s):  
Immune Response ◽  
Nuclear Pore Complex ◽  
Innate Immune ◽  
Nuclear Proteins ◽  
Nuclear Pore ◽  
Cytoplasmic Transport ◽  
Infected Cells ◽  
Main Regulator ◽  
Mature Mrnas ◽  
Replicative Cycle

ABSTRACTViruses hijack cellular proteins and components to be replicated in the host cell and to evade the immune response. Although flaviviruses have a cytoplasmic replicative cycle, some viral proteins such as the capsid (C) and the RNA dependent RNA polymerase, NS5, can reach the nucleus of the infected cells. Considering the important roles of NS5 in viral replication and in the control of the immune response, and its striking presence in the nucleus, the possible functions of this protein in some mechanisms orchestrated by the nucleus was analyzed. We isolated and identified nuclear proteins that interact with NS5; one of them, the DEAD-box RNA helicase DDX5 is relocated to the cytoplasm and degraded during infection with DENV, which correlates with its function in IFN dependent response. Since DDX5 and many other proteins are relocated from the nucleus to the cytoplasm during flavivirus infection, the integrity and function of the main regulator of the nuclear-cytoplasmic transport, the nuclear pore complex (NPC) was evaluated. We found that during DENV and ZIKV infection nucleoporins (NUPs) such as TPR, Nup153, Nup98, and Nup62 were cleavaged/degraded. The protease NS2B-NS3 induces NUPs degradation and it causes a dramatic inhibition of mature mRNAs export to the cytoplasm but not the export of DDX5 protein, which is dependent on NS5. Here we describe for the first time that the NS3 and NS5 proteins from flavivirus play novel functions hijacking the NPC and some nuclear proteins relevant in triggering immune response pathways, inducing a favorable environment for viral replication.IMPORTANCEViruses, as intracellular obligate parasites, hijack cellular components to enter and replicate in infected cells. Remarkably, in many cases, viruses hijack molecules with crucial functions for the cells. Here it is described how RNA viruses such as DENV and ZIKV, with a cytoplasmic replicative cycle, use NS3 and NS5, two of their unique non-structural proteins with enzymatic activity, to modulate nuclear-cytoplasmic transport. We found that NS3 disrupts the nuclear pore complex, the main regulator in nuclear-cytoplasmic transport, causing a strong reduction in the amount of mature mRNAs in the cytoplasm and an inhibition in innate immune response. Additionally, NS5 induces the relocation of nuclear proteins to the cytoplasm such as DDX5, involved in immune response, which is later degraded by NS3. These findings allow the understanding of crucial mechanisms that viruses use to deal with the control of the immune response to grant the production of new viral particles.

scholarly journals Structure-function analysis of Arabidopsis TOPLESS reveals fundamental conservation of repression mechanisms across eukaryotes

2020 ◽  
Author(s):  
Alexander R. Leydon ◽  
Wei Wang ◽  
Hardik P. Gala ◽  
Sabrina Gilmour ◽  
Samuel Juarez-Solis ◽  
...  
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Function Analysis ◽  
Structure And Function ◽  
Environmental Cues ◽  
Auxin Response ◽  
Middle Domain ◽  
N Terminus ◽  
And Function ◽  
The Relationship ◽  
Repression Domain

SummaryThe plant corepressor TOPLESS (TPL) is recruited to a large number of loci that are selectively induced in response to developmental or environmental cues, yet the mechanisms by which it inhibits expression in the absence of these stimuli is poorly understood. Previously, we had used the N-terminus of Arabidopsis thaliana TPL to enable repression of a synthetic auxin response circuit in Saccharomyces cerevisiae (yeast). Here, we leveraged the yeast system to interrogate the relationship between TPL structure and function, specifically scanning for repression domains. We identified a potent repression domain in Helix 8 located within the CRA domain, which directly interacted with the Mediator middle domain subunits Med21 and Med10. Interactions between TPL and Mediator were required to fully repress transcription in both yeast and plants. In contrast, we found that multimer formation, a conserved feature of many corepressors, had minimal influence on the repression strength of TPL.

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