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Frataxin

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https://www.readbyqxmd.com/read/28634302/structure-of-human-fe-s-assembly-subcomplex-reveals-unexpected-cysteine-desulfurase-architecture-and-acyl-acp-isd11-interactions
#1
Seth A Cory, Jonathan G Van Vranken, Edward J Brignole, Shachin Patra, Dennis R Winge, Catherine L Drennan, Jared Rutter, David P Barondeau
In eukaryotes, sulfur is mobilized for incorporation into multiple biosynthetic pathways by a cysteine desulfurase complex that consists of a catalytic subunit (NFS1), LYR protein (ISD11), and acyl carrier protein (ACP). This NFS1-ISD11-ACP (SDA) complex forms the core of the iron-sulfur (Fe-S) assembly complex and associates with assembly proteins ISCU2, frataxin (FXN), and ferredoxin to synthesize Fe-S clusters. Here we present crystallographic and electron microscopic structures of the SDA complex coupled to enzyme kinetic and cell-based studies to provide structure-function properties of a mitochondrial cysteine desulfurase...
June 20, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28630009/identification-of-two-frataxin-isoforms-in-zea-mays-structural-and-functional-studies
#2
Celeste Buchensky, Manuel Sánchez, Martin Carrillo, Oscar Palacios, Mercè Capdevila, Jose M Domínguez-Vera, Maria V Busi, Sílvia Atrian, Maria A Pagani, Diego F Gomez-Casati
Frataxin is a ubiquitous protein that plays a role in Fe-S cluster biosynthesis and iron and heme metabolism, although its molecular functions are not entirely clear. In non-photosynthetic eukaryotes, frataxin is encoded by a single gene, and the protein localizes to mitochondria. Here we report the presence of two functional frataxin isoforms in Zea mays, ZmFH-1 and ZmFH-2. We confirmed our previous findings regarding plant frataxins: both proteins have dual localization in mitochondria and chloroplasts. Physiological, biochemical and biophysical studies show some differences in the expression pattern, protection against oxidants and in the aggregation state of both isoforms, suggesting that the two frataxin homologs would play similar but not identical roles in plant cell metabolism...
June 16, 2017: Biochimie
https://www.readbyqxmd.com/read/28580734/sars-unique-fold-in-the-rousettus-bat-coronavirus-hku9
#3
Robert G Hammond, Xuan Tan, Margaret A Johnson
The coronavirus nonstructural protein 3 (nsp3) is a multifunctional protein that comprises multiple structural domains. This protein assists viral polyprotein cleavage, host immune interference, and may play other roles in genome replication or transcription. Here, we report the solution NMR structure of a protein from the "SARS-unique region" of the bat coronavirus HKU9. The protein contains a frataxin fold or double-wing motif, which is an α + β fold that is associated with protein/protein interactions, DNA binding, and metal ion binding...
June 5, 2017: Protein Science: a Publication of the Protein Society
https://www.readbyqxmd.com/read/28573291/mechanisms-of-iron-and-copper-frataxin-interactions
#4
T H L Han, J M Camadro, R Santos, E Lesuisse, J M El Hage Chahine, N T Ha-Duong
Frataxin is a mitochondrial protein whose deficiency is the cause of Friedreich's ataxia, a hereditary neurodegenerative disease. This protein plays a role in iron-sulfur cluster biosynthesis, protection against oxidative stress and iron metabolism. In an attempt to provide a better understanding of the role played by metals in its metabolic functions, the mechanisms of mitochondrial metal binding to frataxin in vitro have been investigated. A purified recombinant yeast frataxin homolog Yfh1 binds two Cu(ii) ions with a Kd1(Cu(II)) of 1...
June 2, 2017: Metallomics: Integrated Biometal Science
https://www.readbyqxmd.com/read/28562313/friedreich-s-ataxia-induced-pluripotent-stem-cell-derived-cardiomyocytes-display-electrophysiological-abnormalities-and-calcium-handling-deficiency
#5
Duncan E Crombie, Claire L Curl, Antonia Ja Raaijmakers, Priyadharshini Sivakumaran, Tejal Kulkarni, Raymond Cb Wong, Itsunari Minami, Marguerite V Evans-Galea, Shiang Y Lim, Lea Delbridge, Louise A Corben, Mirella Dottori, Norio Nakatsuji, Ian A Trounce, Alex W Hewitt, Martin B Delatycki, Martin F Pera, Alice Pébay
We sought to identify the impacts of Friedreich's ataxia (FRDA) on cardiomyocytes. FRDA is an autosomal recessive degenerative condition with neuronal and non-neuronal manifestations, the latter including progressive cardiomyopathy of the left ventricle, the leading cause of death in FRDA. Little is known about the cellular pathogenesis of FRDA in cardiomyocytes. Induced pluripotent stem cells (iPSCs) were derived from three FRDA individuals with characterized GAA repeats. The cells were differentiated into cardiomyocytes to assess phenotypes...
May 30, 2017: Aging
https://www.readbyqxmd.com/read/28548666/zinc-and-the-iron-donor-frataxin-regulate-oligomerization-of-the-scaffold-protein-to-form-new-fe-s-cluster-assembly-centers
#6
B K Galeano, W Ranatunga, O Gakh, D Y Smith, J R Thompson, G Isaya
Early studies of the bacterial Fe-S cluster assembly system provided structural details for how the scaffold protein and the cysteine desulfurase interact. This work and additional work on the yeast and human systems elucidated a conserved mechanism for sulfur donation but did not provide any conclusive insights into the mechanism for iron delivery from the iron donor, frataxin, to the scaffold. We previously showed that oligomerization is a mechanism by which yeast frataxin (Yfh1) can promote assembly of the core machinery for Fe-S cluster synthesis both in vitro and in cells, in such a manner that the scaffold protein, Isu1, can bind to Yfh1 independent of the presence of the cysteine desulfurase, Nfs1...
June 21, 2017: Metallomics: Integrated Biometal Science
https://www.readbyqxmd.com/read/28542596/progressive-mitochondrial-protein-lysine-acetylation-and-heart-failure-in-a-model-of-friedreich-s-ataxia-cardiomyopathy
#7
Amanda R Stram, Gregory R Wagner, Brian D Fogler, P Melanie Pride, Matthew D Hirschey, R Mark Payne
INTRODUCTION: The childhood heart disease of Friedreich's Ataxia (FRDA) is characterized by hypertrophy and failure. It is caused by loss of frataxin (FXN), a mitochondrial protein involved in energy homeostasis. FRDA model hearts have increased mitochondrial protein acetylation and impaired sirtuin 3 (SIRT3) deacetylase activity. Protein acetylation is an important regulator of cardiac metabolism and loss of SIRT3 increases susceptibility of the heart to stress-induced cardiac hypertrophy and ischemic injury...
2017: PloS One
https://www.readbyqxmd.com/read/28516908/an-optimized-strategy-to-measure-protein-stability-highlights-differences-between-cold-and-hot-unfolded-states
#8
Caterina Alfano, Domenico Sanfelice, Stephen R Martin, Annalisa Pastore, Piero Andrea Temussi
Macromolecular crowding ought to stabilize folded forms of proteins, through an excluded volume effect. This explanation has been questioned and observed effects attributed to weak interactions with other cell components. Here we show conclusively that protein stability is affected by volume exclusion and that the effect is more pronounced when the crowder's size is closer to that of the protein under study. Accurate evaluation of the volume exclusion effect is made possible by the choice of yeast frataxin, a protein that undergoes cold denaturation above zero degrees, because the unfolded form at low temperature is more expanded than the corresponding one at high temperature...
May 18, 2017: Nature Communications
https://www.readbyqxmd.com/read/28504123/erythropoietin-and-small-molecule-agonists-of-the-tissue-protective-erythropoietin-receptor-increase-fxn-expression-in-neuronal-cells-in%C3%A2-vitro-and-in-fxn-deficient-kiko-mice-in%C3%A2-vivo
#9
James L Miller, Myriam Rai, Normand L Frigon, Massimo Pandolfo, Juha Punnonen, Jeffrey R Spencer
Friedreich's ataxia (FA) is a progressive neurodegenerative disease caused by reduced levels of the mitochondrial protein frataxin (FXN). Recombinant human erythropoietin (rhEPO) increased FXN protein in vitro and in early clinical studies, while no published reports evaluate rhEPO in animal models of FA. STS-E412 and STS-E424 are novel small molecule agonists of the tissue-protective, but not the erythropoietic EPO receptor. We find that rhEPO, STS-E412 and STS-E424 increase FXN expression in vitro and in vivo...
May 11, 2017: Neuropharmacology
https://www.readbyqxmd.com/read/28456899/mesenchymal-stem-cell-derived-factors-restore-function-to-human-frataxin-deficient-cells
#10
Kevin Kemp, Rimi Dey, Amelia Cook, Neil Scolding, Alastair Wilkins
Friedreich's ataxia is an inherited neurological disorder characterised by mitochondrial dysfunction and increased susceptibility to oxidative stress. At present, no therapy has been shown to reduce disease progression. Strategies being trialled to treat Friedreich's ataxia include drugs that improve mitochondrial function and reduce oxidative injury. In addition, stem cells have been investigated as a potential therapeutic approach. We have used siRNA-induced knockdown of frataxin in SH-SY5Y cells as an in vitro cellular model for Friedreich's ataxia...
April 29, 2017: Cerebellum
https://www.readbyqxmd.com/read/28451558/comparison-of-two-different-pcr-based-methods-for-detection-of-gaa-expansions-in-frataxin-gene
#11
Mona Entezam, Akbar Amirfiroozi, Mansoureh Togha, Mohammad Keramatipour
BACKGROUND: Expansion of GAA trinucleotide repeats is the molecular basis of Friedreich's ataxia (FRDA). Precise detection of the GAA expansion repeat in frataxin gene has always been a challenge. Different molecular methods have been suggested for detection of GAA expansion, including; short-PCR, long-PCR, Triplet repeat primed-PCR (TP-PCR) and southern blotting. The aim of study was to evaluate two PCR-based methods, TP-PCR and long-PCR, and to explore the use of TP-PCR accompanying with long-PCR for accurate genotyping of FRDA patients...
February 2017: Iranian Journal of Public Health
https://www.readbyqxmd.com/read/28444186/frataxin-deficiency-impairs-mitochondrial-biogenesis-in-cells-mice-and-humans
#12
Mittal J Jasoliya, Marissa Z McMackin, Chelsea K Henderson, Susan L Perlman, Gino A Cortopassi
Friedreich's ataxia (FRDA) is a neurodegenerative disease caused by inherited deficiency of the mitochondrial protein Frataxin (FXN), which has no approved therapy and is an area in which biomarkers are needed for clinical development. Here we investigated the consequences of FXN deficiency in patient derived FRDA fibroblast cell models, the FRDA mouse model KIKO, and in whole blood collected from FRDA patients. We observed decreased mitochondrial copy number in all the three FRDA models tested: cells, mice and patient blood...
April 21, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28412459/no-changes-in-heme-synthesis-in-human-friedreich%C3%A2-s-ataxia-erythroid-progenitor-cells
#13
Hannes Steinkellner, Himanshu Narayan Singh, Martina U Muckenthaler, Hans Goldenberg, Rajeswari R Moganty, Barbara Scheiber-Mojdehkar, Brigitte Sturm
Friedreich's ataxia (FRDA) is a neurodegenerative disease caused by reduced expression of the protein frataxin. Frataxin is thought to play a role in iron-sulfur cluster biogenesis and heme synthesis. In this study, we used erythroid progenitor stem cells obtained from FRDA patients and healthy donors to investigate the putative role, if any, of frataxin deficiency in heme synthesis. We used electrochemiluminescence and qRT-PCR for frataxin protein and mRNA quantification. We used atomic absorption spectrophotometry for iron levels and a photometric assay for hemoglobin levels...
July 20, 2017: Gene
https://www.readbyqxmd.com/read/28405347/friedreich-ataxia-current-status-and-future-prospects
#14
REVIEW
Katrin Bürk
Friedreich ataxia (FA) represents the most frequent type of inherited ataxia. Most patients carry homozygous GAA expansions in the first intron of the frataxin gene on chromosome 9. Due to epigenetic alterations, frataxin expression is significantly reduced. Frataxin is a mitochondrial protein. Its deficiency leads to mitochondrial iron overload, defective energy supply and generation of reactive oxygen species. This review gives an overview over clinical and genetic aspects of FA and discusses current concepts of frataxin biogenesis and function as well as new therapeutic strategies...
2017: Cerebellum & Ataxias
https://www.readbyqxmd.com/read/28286293/a-role-for-astrocytes-in-cerebellar-deficits-in-frataxin-deficiency-protection-by-insulin-like-growth-factor-i
#15
C Franco, L Genis, J A Navarro, P Perez-Domper, A M Fernandez, S Schneuwly, I Torres Alemán
Inherited neurodegenerative diseases such as Friedreich's ataxia (FRDA), produced by deficiency of the mitochondrial chaperone frataxin (Fxn), shows specific neurological deficits involving different subset of neurons even though deficiency of Fxn is ubiquitous. Because astrocytes are involved in neurodegeneration, we analyzed whether they are also affected by frataxin deficiency and contribute to the disease. We also tested whether insulin-like growth factor I (IGF-I), that has proven effective in increasing frataxin levels both in neurons and in astrocytes, also exerts in vivo protective actions...
March 7, 2017: Molecular and Cellular Neurosciences
https://www.readbyqxmd.com/read/28282710/early-onset-friedreich-s-ataxia-with-oculomotor-apraxia
#16
Amene Saghazadeh, Sina Hafizi, Firouzeh Hosseini, Mahmoud Reza Ashrafi, Nima Rezaei
Friedreich's ataxia (FRDA) is a rare autosomal recessive spinocerebellar ataxia which in the majority of cases is associated with a GAA-trinucleotide repeat expansion in the first intron of Frataxin gene located on chromosome 9. The clinical features include progressive gait and limb ataxia, cerebellar dysarthria, neuropathy, optic atrophy, and loss of vibration and proprioception. Ataxia with ocular motor apraxia type 1 (AOA1) is another autosomal recessive cerebellar ataxia which is associated with oculomotor apraxia, hypoalbuminaemia, and hypercholesterolemia...
February 2017: Acta Medica Iranica
https://www.readbyqxmd.com/read/28271877/the-n-terminus-of-iron-sulfur-cluster-assembly-factor-isd11-is-crucial-for-subcellular-targeting-and-interaction-with-l-cysteine-desulfurase-nfs1
#17
Martin Friemel, Zvonimir Marelja, Kuanyu Li, Silke Leimkühler
Assembly of iron-sulfur (FeS) clusters is an important process in living cells. The initial sulfur mobilization step for FeS cluster biosynthesis is catalyzed by l-cysteine desulfurase NFS1, a reaction that is localized in mitochondria in humans. In humans, the function of NFS1 depends on the ISD11 protein, which is required to stabilize its structure. The NFS1/ISD11 complex further interacts with scaffold protein ISCU and regulator protein frataxin, thereby forming a quaternary complex for FeS cluster formation...
March 28, 2017: Biochemistry
https://www.readbyqxmd.com/read/28228265/e3-ligase-rnf126-directly-ubiquitinates-frataxin-promoting-its-degradation-identification-of-a-potential-therapeutic-target-for-friedreich-ataxia
#18
Monica Benini, Silvia Fortuni, Ivano Condò, Giulia Alfedi, Florence Malisan, Nicola Toschi, Dario Serio, Damiano Sergio Massaro, Gaetano Arcuri, Roberto Testi, Alessandra Rufini
Friedreich ataxia (FRDA) is a severe genetic neurodegenerative disease caused by reduced expression of the mitochondrial protein frataxin. To date, there is no therapy to treat this condition. The amount of residual frataxin critically affects the severity of the disease; thus, attempts to restore physiological frataxin levels are considered therapeutically relevant. Frataxin levels are controlled by the ubiquitin-proteasome system; therefore, inhibition of the frataxin E3 ligase may represent a strategy to achieve an increase in frataxin levels...
February 21, 2017: Cell Reports
https://www.readbyqxmd.com/read/28024081/deletion-of-the-gaa-repeats-from-the-human-frataxin-gene-using-the-crispr-cas9-system-in-yg8r-derived-cells-and-mouse-models-of-friedreich-ataxia
#19
D L Ouellet, K Cherif, J Rousseau, J P Tremblay
The Friedreich ataxia is a monogenic disease due to a hyperexpanded GAA triplet located within the first intron of the frataxin gene that causes transcriptional issues. The resulting frataxin protein deficiency leads to a Fe-S cluster biosynthesis dysfunction in the mitochondria and to oxidative stress and cell death. Here we use the CRISPR-Cas9 system to remove the mutated GAA expansion and restore the frataxin gene transcriptional activity and protein level. Both YG8R and YG8sR mouse models and cell lines derived from these mice were used to CRISPR-edited successfully the GAA expansion in vitro and in vivo...
May 2017: Gene Therapy
https://www.readbyqxmd.com/read/28009062/cytokine-therapy-mediated-neuroprotection-in-a-friedreich-s-ataxia-mouse-model
#20
Kevin C Kemp, Nadia Cerminara, Kelly Hares, Juliana Redondo, Amelia J Cook, Harry R Haynes, Bronwen R Burton, Mark Pook, Richard Apps, Neil J Scolding, Alastair Wilkins
OBJECTIVES: Friedreich's ataxia is a devastating neurological disease currently lacking any proven treatment. We studied the neuroprotective effects of the cytokines, granulocyte-colony stimulating factor (G-CSF) and stem cell factor (SCF) in a humanized murine model of Friedreich's ataxia. METHODS: Mice received monthly subcutaneous infusions of cytokines while also being assessed at monthly time points using an extensive range of behavioral motor performance tests...
February 2017: Annals of Neurology
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