scholarly journals Mammalian Homologue NME3 of DYNAMO1 Regulates Peroxisome Division

2020 ◽  
Vol 21 (21) ◽  
pp. 8040
Author(s):  
Masanori Honsho ◽  
Yuichi Abe ◽  
Yuuta Imoto ◽  
Zee-Fen Chang ◽  
Hanna Mandel ◽  
...  
Keyword(s):  
Nucleoside Diphosphate Kinase ◽  
Cyanidioschyzon Merolae ◽  
Homozygous Mutation ◽  
Ndp Kinase ◽  
Peroxisomal Membrane ◽  
Physiological Importance ◽  
In The Wild ◽  
Ethanolamine Plasmalogens ◽  
Mammalian Homologue ◽  
Peroxisome Division

Peroxisomes proliferate by sequential processes comprising elongation, constriction, and scission of peroxisomal membrane. It is known that the constriction step is mediated by a GTPase named dynamin-like protein 1 (DLP1) upon efficient loading of GTP. However, mechanism of fuelling GTP to DLP1 remains unknown in mammals. We earlier show that nucleoside diphosphate (NDP) kinase-like protein, termed dynamin-based ring motive-force organizer 1 (DYNAMO1), generates GTP for DLP1 in a red alga, Cyanidioschyzon merolae. In the present study, we identified that nucleoside diphosphate kinase 3 (NME3), a mammalian homologue of DYNAMO1, localizes to peroxisomes. Elongated peroxisomes were observed in cells with suppressed expression of NME3 and fibroblasts from a patient lacking NME3 due to the homozygous mutation at the initiation codon of NME3. Peroxisomes proliferated by elevation of NME3 upon silencing the expression of ATPase family AAA domain containing 1, ATAD1. In the wild-type cells expressing catalytically-inactive NME3, peroxisomes were elongated. These results suggest that NME3 plays an important role in peroxisome division in a manner dependent on its NDP kinase activity. Moreover, the impairment of peroxisome division reduces the level of ether-linked glycerophospholipids, ethanolamine plasmalogens, implying the physiological importance of regulation of peroxisome morphology.

Novel ASCC1 mutations causing prenatal-onset muscle weakness with arthrogryposis and congenital bone fractures

2018 ◽  
Vol 56 (9) ◽  
pp. 617-621 ◽  
Author(s):  
Johann Böhm ◽  
Edoardo Malfatti ◽  
Emily Oates ◽  
Kristi Jones ◽  
Guy Brochier ◽  
...  
Keyword(s):  
Muscle Weakness ◽  
Bone Fractures ◽  
Bone Development ◽  
Homozygous Mutation ◽  
Transcriptional Coactivator ◽  
Related Disorder ◽  
Physiological Importance ◽  
Muscle Histology ◽  
Muscle Biopsies ◽  
Fetal Muscle

BackgroundThe activating signal cointegrator 1 (ASC-1) complex acts as a transcriptional coactivator for a variety of transcription factors and consists of four subunits: ASCC1, ASCC2, ASCC3 and TRIP4. A single homozygous mutation in ASCC1 has recently been reported in two families with a severe muscle and bone disorder.ObjectiveWe aim to contribute to a better understanding of the ASCC1-related disorder.MethodsHere, we provide a clinical, histological and genetic description of three additional ASCC1 families.ResultsAll patients presented with severe prenatal-onset muscle weakness, neonatal hypotonia and arthrogryposis, and congenital bone fractures. The muscle biopsies from the affected infants revealed intense oxidative rims beneath the sarcolemma and scattered remnants of sarcomeres with enlarged Z-bands, potentially representing a histopathological hallmark of the disorder. Sequencing identified recessive nonsense or frameshift mutations in ASCC1, including two novel mutations.ConclusionOverall, this work expands the ASCC1 mutation spectrum, sheds light on the muscle histology of the disorder and emphasises the physiological importance of the ASC-1 complex in fetal muscle and bone development.

scholarly journals A Role for Fis1 in Both Mitochondrial and Peroxisomal Fission in Mammalian Cells

2005 ◽  
Vol 16 (11) ◽  
pp. 5077-5086 ◽  
Author(s):  
Annett Koch ◽  
Yisang Yoon ◽  
Nina A. Bonekamp ◽  
Mark A. McNiven ◽  
Michael Schrader
Keyword(s):  
Mammalian Cells ◽  
Small Interfering Rna ◽  
Transmembrane Domain ◽  
Mitochondrial Fission ◽  
Ectopic Expression ◽  
Mammalian Homologue ◽  
Necessary And Sufficient ◽  
Interfering Rna ◽  
Peroxisome Division

The mammalian dynamin-like protein DLP1/Drp1 has been shown to mediate both mitochondrial and peroxisomal fission. In this study, we have examined whether hFis1, a mammalian homologue of yeast Fis1, which has been shown to participate in mitochondrial fission by an interaction with DLP1/Drp1, is also involved in peroxisomal growth and division. We show that hFis1 localizes to peroxisomes in addition to mitochondria. Through differential tagging and deletion experiments, we demonstrate that the transmembrane domain and the short C-terminal tail of hFis1 is both necessary and sufficient for its targeting to peroxisomes and mitochondria, whereas the N-terminal region is required for organelle fission. hFis1 promotes peroxisome division upon ectopic expression, whereas silencing of Fis1 by small interfering RNA inhibited fission and caused tubulation of peroxisomes. These findings provide the first evidence for a role of Fis1 in peroxisomal fission and suggest that the fission machinery of mitochondria and peroxisomes shares common components.

Interaction of Phosphates of the Acyclic Nucleoside Phosphonates with Nucleoside Diphosphate Kinase from Yeast and Bovine Liver

2006 ◽  
Vol 71 (1) ◽  
pp. 35-43 ◽  
Author(s):  
Květoslava Horská ◽  
Ivan Votruba ◽  
Antonín Holý
Keyword(s):  
Nucleoside Diphosphate Kinase ◽  
Bovine Liver ◽  
Kinetic Constants ◽  
Aliphatic Chain ◽  
Ndp Kinase ◽  
Hydroxymethyl Group ◽  
Acyclic Nucleoside Phosphonates ◽  
Acyclic Nucleoside ◽  
Acyclic Nucleoside Phosphonate

The ability of monophosphates of selected acyclic nucleoside phosphonates to serve as substrates for the title NDP kinases was studied. Comparison of the kinetic constants (KM, Vmax, kcat and kcat/KM) estimates indicates that the yeast enzyme catalyzes the phosphorylation of purine and pyrimidine acyclic nucleoside phosphate phosphonates of the 9-[2-(phosphonomethoxy)ethyl] and/or 9-[2-(phosphonomethoxy)propyl] series more efficiently than bovine liver NDP kinase. Yeast enzyme preferentially phosphorylates phosphates of the (phosphono- methoxyalkyl)guanines rather than their adenine counterparts; both enzymes phosphorylate R-enantiomers of the 9-[2-(phosphonomethoxy)propyl] series more efficiently than the corresponding S-enantiomers. Substitution of the aliphatic chain at the position 3 with hydroxymethyl group considerably increases the substrate activity of phosphate of acyclic nucleoside phosphonate. The resulting substrate activity (kcat/KM ratio) of all acyclic nucleoside phosphonate phosphates studied is three to five orders of magnitude lower than that for natural NDPs.

Deoxyribonucleotide Biosynthesis in Green Algae. S Phase-Specific Thymidylate Kinase and Unspecific Nucleoside Diphosphate Kinase in Scenedesmus obliquus

1988 ◽  
Vol 43 (5-6) ◽  
pp. 377-385 ◽  
Author(s):  
Beate Klein ◽  
Hartmut Follmann
Keyword(s):  
Cell Cycle ◽  
Molecular Weight ◽  
Green Algae ◽  
De Novo ◽  
Scenedesmus Obliquus ◽  
Nucleoside Diphosphate Kinase ◽  
S Phase ◽  
Ndp Kinase ◽  
Thymidylate Kinase

NDP kinase and thymidylate kinase are essential for DNA precursor formation in that they phosphorylate the products of de novo deoxyribonucleotide biosynthesis, deoxyribonucleoside 5′-diphosphates and thymidine 5′-monophosphate to the corresponding triphosphates which then serve as DNA polymerase substrates. The two enzymes have been measured in synchronous cultures of the green algae, S. obliquus. Thymidylate kinase exhibits an activity peak at the 11 -12th hour of the 24-hour cell cycle, coinciding with DNA synthesis. Enzyme activity is markedly stimulated in presence of fluorodeoxyuridine in the culture medium. This behaviour of dTMP kinase is very similar to that of three other S phase-specific peak enzymes previously analyzed in synchronous algae, viz. ribonucleotide reductase, thymidylate synthase, and dihydrofolate reductase. In contrast, NDP kinase exhibits high and constant activity through the entire cell cycle. The two kinases have been isolated from cell-free extracts, and separated from each other by chromatography on Blue Sepharose. The peak enzyme, dTMP kinase, has been purified to near homogeneity and its catalytic properties are described; the molecular weight is 56,000. NDP kinase activity is separable into two enzyme fractions, both of molecular weight 100,000 (or higher), which are unspecific with respect to ribonucleotide and deoxyribonucleotide substrates. Characterization and purification of the whole series of deoxyribonucleotide-synthesizing enzymes from one organism provides a basis for in vitro experiments towards reconstitution of an S phase-specific DNA precursor/DNA replication multienzyme aggregate.

scholarly journals A signal from inside the peroxisome initiates its division by promoting the remodeling of the peroxisomal membrane

2007 ◽  
Vol 177 (2) ◽  
pp. 289-303 ◽  
Author(s):  
Tong Guo ◽  
Christopher Gregg ◽  
Tatiana Boukh-Viner ◽  
Pavlo Kyryakov ◽  
Alexander Goldberg ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Cytoskeletal Proteins ◽  
Matrix Proteins ◽  
Peroxisome Biogenesis ◽  
Peroxisomal Membrane ◽  
Membrane Fission ◽  
The Matrix ◽  
Complete Set ◽  
Acyl Coa Oxidase ◽  
Peroxisome Division

We define the dynamics of spatial and temporal reorganization of the team of proteins and lipids serving peroxisome division. The peroxisome becomes competent for division only after it acquires the complete set of matrix proteins involved in lipid metabolism. Overloading the peroxisome with matrix proteins promotes the relocation of acyl-CoA oxidase (Aox), an enzyme of fatty acid β-oxidation, from the matrix to the membrane. The binding of Aox to Pex16p, a membrane-associated peroxin required for peroxisome biogenesis, initiates the biosynthesis of phosphatidic acid and diacylglycerol (DAG) in the membrane. The formation of these two lipids and the subsequent transbilayer movement of DAG initiate the assembly of a complex between the peroxins Pex10p and Pex19p, the dynamin-like GTPase Vps1p, and several actin cytoskeletal proteins on the peroxisomal surface. This protein team promotes membrane fission, thereby executing the terminal step of peroxisome division.

The three-dimensional structures of two isoforms of nucleoside diphosphate kinase from bovine retina

1999 ◽  
Vol 55 (6) ◽  
pp. 1127-1135 ◽  
Author(s):  
Jane E. Ladner ◽  
Najmoutin G. Abdulaev ◽  
Dmitri L. Kakuev ◽  
Mária Tordová ◽  
Kevin D. Ridge ◽  
...  
Keyword(s):  
Active Site ◽  
Three Dimensional ◽  
Nucleoside Diphosphate Kinase ◽  
Asymmetric Unit ◽  
Ndp Kinase ◽  
Space Group ◽  
Space Groups ◽  
Bovine Retina ◽  
Biological Sources ◽  
Polypeptide Chains

The crystal structures of two isoforms of nucleoside diphosphate kinase from bovine retina overexpressed in Escherischia coli have been determined to 2.4 Å resolution. Both the isoforms, NBR-A and NBR-B, are hexameric and the fold of the monomer is in agreement with NDP-kinase structures from other biological sources. Although the polypeptide chains of the two isoforms differ by only two residues, they crystallize in different space groups. NBR-A crystallizes in space group P212121 with an entire hexamer in the asymmetric unit, while NBR-B crystallizes in space group P43212 with a trimer in the asymmetric unit. The highly conserved nucleotide-binding site observed in other nucleoside diphosphate kinase structures is also observed here. Both NBR-A and NBR-B were crystallized in the presence of cGMP. The nucleotide is bound with the base in the anti conformation. The NBR-A active site contained both cGMP and GDP each bound at half occupancy. Presumably, NBR-A had retained GDP (or GTP) from the purification process. The NBR-B active site contained only cGMP.

scholarly journals SwoHp, a Nucleoside Diphosphate Kinase, Is Essential in Aspergillus nidulans

2003 ◽  
Vol 2 (6) ◽  
pp. 1169-1177 ◽  
Author(s):  
Xiaorong Lin ◽  
Cory Momany ◽  
Michelle Momany
Keyword(s):  
Aspergillus Nidulans ◽  
Elevated Temperatures ◽  
Nucleoside Diphosphate Kinase ◽  
Temperature Sensitive ◽  
Transferase Activity ◽  
Restrictive Temperature ◽  
Permissive Temperature ◽  
Cell Extracts ◽  
In The Wild ◽  
Chromosome Ii

ABSTRACT The temperature-sensitive swoH1 mutant of Aspergillus nidulans was previously identified in a screen for mutants with defects in polar growth. In the present work, we found that the swoH1 mutant swelled, lysed, and did not produce conidia during extended incubation at the restrictive temperature. When shifted from the permissive to the restrictive temperature, swoH1 showed the temperature-sensitive swelling phenotype only after 8 h at the higher temperature. The swoH gene was mapped to chromosome II and cloned by complementation of the temperature-sensitive phenotype. The sequence showed that swoH encodes a homologue of nucleoside diphosphate kinases (NDKs) from other organisms. Deletion experiments showed that the swoH gene is essential. A hemagglutinin-SwoHp fusion complemented the mutant phenotype, and the purified fusion protein possessed phosphate transferase activity in thin-layer chromatography assays. Sequencing of the mutant allele showed a predicted V83F change. Structural modeling suggested that the swoH1 mutation would lead to perturbation of the NDK active site. Crude cell extracts from the swoH1 mutant grown at the permissive temperature had ∼20% of the NDK activity seen in the wild type and did not show any decrease in activity when assayed at higher temperatures. Though the data are not conclusive, the lack of temperature-sensitive NDK activity in the swoH1 mutant raises the intriguing possibility that the SwoH NDK is required for growth at elevated temperatures rather than for polarity maintenance.

scholarly journals Two separate functions of NME3 critical for cell survival underlie a neurodegenerative disorder

2018 ◽  
Vol 116 (2) ◽  
pp. 566-574 ◽  
Author(s):  
Chih-Wei Chen ◽  
Hong-Ling Wang ◽  
Ching-Wen Huang ◽  
Chang-Yu Huang ◽  
Wai Keong Lim ◽  
...  
Keyword(s):  
Cell Survival ◽  
Neurodegenerative Disorder ◽  
Mitochondrial Dynamics ◽  
Initiation Codon ◽  
Metabolic Adaptation ◽  
Mitochondrial Outer Membrane ◽  
Homozygous Mutation ◽  
Glucose Starvation ◽  
Wild Type ◽  
Ndp Kinase

We report a patient who presented with congenital hypotonia, hypoventilation, and cerebellar histopathological alterations. Exome analysis revealed a homozygous mutation in the initiation codon of the NME3 gene, which encodes an NDP kinase. The initiation-codon mutation leads to deficiency in NME3 protein expression. NME3 is a mitochondrial outer-membrane protein capable of interacting with MFN1/2, and its depletion causes dysfunction in mitochondrial dynamics. Consistently, the patient’s fibroblasts were characterized by a slow rate of mitochondrial dynamics, which was reversed by expression of wild-type or catalytic-dead NME3. Moreover, glucose starvation caused mitochondrial fragmentation and cell death in the patient’s cells. The expression of wild-type and catalytic-dead but not oligomerization-attenuated NME3 restored mitochondrial elongation. However, only wild-type NME3 sustained ATP production and viability. Thus, the separate functions of NME3 in mitochondrial fusion and NDP kinase cooperate in metabolic adaptation for cell survival in response to glucose starvation. Given the critical role of mitochondrial dynamics and energy requirements in neuronal development, the homozygous mutation in NME3 is linked to a fatal mitochondrial neurodegenerative disorder.

scholarly journals Pex20p of the Yeast Yarrowia lipolytica Is Required for the Oligomerization of Thiolase in the Cytosol and for Its Targeting to the Peroxisome

1998 ◽  
Vol 142 (2) ◽  
pp. 403-420 ◽  
Author(s):  
Vladimir I. Titorenko ◽  
Jennifer J. Smith ◽  
Rachel K. Szilard ◽  
Richard A. Rachubinski
Keyword(s):  
Yarrowia Lipolytica ◽  
High Speed ◽  
Matrix Protein ◽  
Peroxisomal Membrane ◽  
Amino Terminal ◽  
Peroxisomal Targeting ◽  
In The Wild ◽  
Targeting Signal ◽  
Polypeptide Chains ◽  
Yeast Yarrowia Lipolytica

Pex mutants are defective in peroxisome assembly. In the pex20-1 mutant strain of the yeast Yarrowia lipolytica, the peroxisomal matrix protein thiolase is mislocalized exclusively to the cytosol, whereas the import of other peroxisomal proteins is unaffected. The PEX20 gene was isolated by functional complementation of the pex20-1 strain and encodes a protein, Pex20p, of 424 amino acids (47,274 D). Despite its role in the peroxisomal import of thiolase, which is targeted by an amino-terminal peroxisomal targeting signal-2 (PTS2), Pex20p does not exhibit homology to Pex7p, which acts as the PTS2 receptor. Pex20p is mostly cytosolic, whereas 4–8% is associated with high-speed (200,000 g) pelletable peroxisomes. In the wild-type strain, all newly synthesized thiolase is associated with Pex20p in a heterotetrameric complex composed of two polypeptide chains of each protein. This association is independent of PTS2. Pex20p is required for both the oligomerization of thiolase in the cytosol and its targeting to the peroxisome. Our data suggest that monomeric Pex20p binds newly synthesized monomeric thiolase in the cytosol and promotes the formation of a heterotetrameric complex of these two proteins, which could further bind to the peroxisomal membrane. Translocation of the thiolase homodimer into the peroxisomal matrix would release Pex20p monomers back to the cytosol, thereby permitting a new cycle of binding-oligomerization-targeting-release for Pex20p and thiolase.

scholarly journals PEX11α Is Required for Peroxisome Proliferation in Response to 4-Phenylbutyrate but Is Dispensable for Peroxisome Proliferator-Activated Receptor Alpha-Mediated Peroxisome Proliferation

2002 ◽  
Vol 22 (23) ◽  
pp. 8226-8240 ◽  
Author(s):  
Xiaoling Li ◽  
Eveline Baumgart ◽  
Gao-Xiang Dong ◽  
James C. Morrell ◽  
Gerardo Jimenez-Sanchez ◽  
...  
Keyword(s):  
Membrane Proteins ◽  
Gene Overexpression ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferation ◽  
Peroxisomal Membrane ◽  
Peroxisome Proliferator Activated Receptor ◽  
Physiological Functions ◽  
Peroxisomal Protein ◽  
Receptor Alpha ◽  
Peroxisome Division

ABSTRACT The PEX11 peroxisomal membrane proteins promote peroxisome division in multiple eukaryotes. As part of our effort to understand the molecular and physiological functions of PEX11 proteins, we disrupted the mouse PEX11α gene. Overexpression of PEX11α is sufficient to promote peroxisome division, and a class of chemicals known as peroxisome proliferating agents (PPAs) induce the expression of PEX11α and promote peroxisome division. These observations led to the hypothesis that PPAs induce peroxisome abundance by enhancing PEX11α expression. The phenotypes of PEX11α−/− mice indicate that this hypothesis remains valid for a novel class of PPAs that act independently of peroxisome proliferator-activated receptor alpha (PPARα) but is not valid for the classical PPAs that act as activators of PPARα. Furthermore, we find that PEX11α−/− mice have normal peroxisome abundance and that cells lacking both PEX11α and PEX11β, a second mammalian PEX11 gene, have no greater defect in peroxisome abundance than do cells lacking only PEX11β. Finally, we report the identification of a third mammalian PEX11 gene, PEX11γ, and show that it too encodes a peroxisomal protein.

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