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| Open AccessRefining the pathway of carbide insertion into the nitrogenase M-cluster
Carbide insertion plays a pivotal role in the biosynthesis of M-cluster, the cofactor of nitrogenase. Here the authors further define the pathway for interstitial carbide atom insertion, showing that the SAM-derived methyl group is transferred to a FeS precursor sulfur before hydrogen abstraction via an SN2-type reaction.
- Jared A. Wiig
- , Yilin Hu
- & Markus W. Ribbe
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Article
| Open AccessHydride bridge in [NiFe]-hydrogenase observed by nuclear resonance vibrational spectroscopy
Understanding the catalytic mechanism of redox-active hydrogenases is a key to efficient hydrogen production and consumption. Here, the authors use nuclear resonance vibrational spectroscopy to study [NiFe]-hydrogenase, and observe a bridging hydride structure in an EPR silent intermediate.
- Hideaki Ogata
- , Tobias Krämer
- & Stephen P. Cramer
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Oestrogen sulfotransferase ablation sensitizes mice to sepsis
Sepsis, a systemic inflammatory response to bacterial infection, can lead to organ failure and death. Here, Chai et al.investigate the mechanisms behind the septic response and identify the role of oestrogen sulfotransferase in this process in mice.
- Xiaojuan Chai
- , Yan Guo
- & Wen Xie
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Article
| Open AccessCrystal structure, biochemical and cellular activities demonstrate separate functions of MTH1 and MTH2
Dysfunctional redox regulation in cancer can damage dNTPs so inhibiting dNTP pool sanitizing enzymes, such as MTH1, is a potential cancer treatment. Here, Carter et al.characterize MTH2 (NUDT15) and show that it is not a dNTP sanitizer, and so is unlikely to influence the efficacy of MTH1 inhibitors.
- Megan Carter
- , Ann-Sofie Jemth
- & Pål Stenmark
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Redefining the concept of protease-activated receptors: cathepsin S evokes itch via activation of Mrgprs
Sensory neurons that mediate histamine-independent itch express Mas-related G protein coupled receptors (Mrgprs). Here, Reddy et al.show that the cysteine protease cathepsin S cleaves and activates MrgpcrC11 without the generation of a tethered ligand, in contrast to other protease activated receptors.
- Vemuri B. Reddy
- , Shuohao Sun
- & Ethan A. Lerner
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Article
| Open AccessStructural and dynamic insights into the energetics of activation loop rearrangement in FGFR1 kinase
Receptor tyrosine kinases are key mediators of cell proliferation that have been implicated in several disease states for which they represent promising drug targets. Here the authors determine the thermodynamic basis for the low propensity of FGFR1 to access the DFG-Phe-out conformation required to bind type-II inhibitors.
- Tobias Klein
- , Navratna Vajpai
- & Alexander L. Breeze
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Article
| Open AccessLocking GTPases covalently in their functional states
The cellular function of small GTPases is regulated by switching between active (GTP-bound) and inactive (GDP-bound) states. Here the authors develop nucleotide analogues that can be covalently linked to GTPases via a strategically placed cysteine residue to lock the target GTPase in defined activation states.
- David Wiegandt
- , Sophie Vieweg
- & Roger S. Goody
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Article
| Open AccessSpecificity and catalysis hardwired at the RNA–protein interface in a translational proofreading enzyme
The editing domain of aminoacyl-tRNA synthetases is responsible for removing non-cognate amino acids from mischarged tRNAs. Here the authors show that the D-aminoacyl-tRNA deacylase fold of archaeal ThrRS does not rely on protein side chains for substrate specificity and catalysis.
- Sadeem Ahmad
- , Sowndarya Muthukumar
- & Rajan Sankaranarayanan
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A primase subunit essential for efficient primer synthesis by an archaeal eukaryotic-type primase
Archaea encode an eukaryotic-type primase comprising a catalytic subunit PriS and a noncatalytic subunit PriL. Here, the authors identify in an archaeon Sulfolobus solfataricus an essential noncatalytic subunit of primase, PriX, that forms PriSLX trimer and increases the efficiency of primer synthesis.
- Bing Liu
- , Songying Ouyang
- & Li Huang
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Article
| Open AccessIdentification of mammalian-adapting mutations in the polymerase complex of an avian H5N1 influenza virus
Understanding the factors that enable some bird flu viruses to infect humans is important for the identification of circulating viruses with higher potential to infect us. Here, Taft et al.identify novel mutations in the polymerase of an avian H5N1 virus that help the virus to replicate in human cells and in mice
- Andrew S. Taft
- , Makoto Ozawa
- & Yoshihiro Kawaoka
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The molecular origin of high DNA-repair efficiency by photolyase
Photolyase is an enzyme responsible for repairing DNA which is damaged after exposure to UV light. Here, the authors use site directed mutagenesis and femtosecond spectroscopy to study how photolyase achieves its maximal repair efficiency.
- Chuang Tan
- , Zheyun Liu
- & Dongping Zhong
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Article
| Open Accessγ-secretase directly sheds the survival receptor BCMA from plasma cells
B-cell maturation antigen (BCMA) regulates the survival of B cells and is essential for the maintenance of long-lived plasma cells. Here, the authors show that γ-secretase directly sheds BCMA from the cell surface and therefore regulates the number of plasma cells.
- Sarah A. Laurent
- , Franziska S. Hoffmann
- & Edgar Meinl
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Article
| Open AccessA network comprising short and long noncoding RNAs and RNA helicase controls mouse retina architecture
The mammalian retina is a modular brain region, in which cell layers are of uniform thickness but the molecular mechanism controlling this process is not well understood. Here the authors identify a regulatory network consisting of the long noncoding RNA Rncr4, RNA helicase Ddx3x and miR-183/96/182 that controls the even distribution of cells across layers.
- Jacek Krol
- , Ilona Krol
- & Witold Filipowicz
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| Open AccessAMPK activation promotes lipid droplet dispersion on detyrosinated microtubules to increase mitochondrial fatty acid oxidation
Lipid droplets (LDs) supply fatty acids to cellular processes and move bidirectionally on microtubules. Here the authors show that nutrient starvation causes dispersal of mitochondria and LD to the periphery of the cell along detyrosinated microtubules and increases LD–mitochondria interactions in an AMPK-dependent manner.
- Albert Herms
- , Marta Bosch
- & Albert Pol
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Interplay between enterobactin, myeloperoxidase and lipocalin 2 regulates E. coli survival in the inflamed gut
Gut inflammation triggers a bloom of certain resident bacteria such as E. coli that can contribute to disease. Here, Singh et al. show that a siderophore produced by E. coliinhibits the antibacterial activity of host myeloperoxidase and enhances bacterial survival in the gut of lab mice.
- Vishal Singh
- , Beng San Yeoh
- & Matam Vijay-Kumar
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Article
| Open AccessDynamic interplay between catalytic and lectin domains of GalNAc-transferases modulates protein O-glycosylation
Polypeptide GalNAc-transferases decorate proteins with dense arrays of O-glycans, which in the case of mucins are essential for their barrier functions. Here the authors present comprehensive structural studies that shed light on the molecular attributes that allow GalNAc-T2 to efficiently carry out dense O-glycosylation.
- Erandi Lira-Navarrete
- , Matilde de las Rivas
- & Ramon Hurtado-Guerrero
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Article
| Open AccessCellulosome stoichiometry in Clostridium cellulolyticum is regulated by selective RNA processing and stabilization
Selective RNA processing and stabilization (SRPS) can regulate bacterial operons, but the process is not well understood. Here, the authors show that the stoichiometry of cellulosome, a 12-subunit protein complex expressed from an operon in Gram-positive Clostridium cellullolyticum, is regulated by SRPS.
- Chenggang Xu
- , Ranran Huang
- & Jian Xu
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| Open AccessDeoxynybomycins inhibit mutant DNA gyrase and rescue mice infected with fluoroquinolone-resistant bacteria
Fluoroquinolone antibiotics are widely used to treat serious bacterial infections, but resistance is an increasing problem. Here the authors describe the synthesis and characterization of novel deoxynybomycin derivatives that exhibit activity against fluoroquinolone-resistant infections in an in vivomodel.
- Elizabeth I. Parkinson
- , Joseph S. Bair
- & Paul J. Hergenrother
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Mouse oocytes depend on BubR1 for proper chromosome segregation but not for prophase I arrest
Mammalian female meiosis is error prone, with error rates increasing with age. Here Touati et al. show that the spindle assembly checkpoint (SAC) protein BubR1, which decreases with age, has multiple roles in meiosis I by controlling SAC, stabilizing the mitotic spindle and timing the onset of anaphase I.
- Sandra A. Touati
- , Eulalie Buffin
- & Katja Wassmann
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The DNA repair endonuclease Mus81 facilitates fast DNA replication in the absence of exogenous damage
Several mechanisms are in place to ensure the accurate and timely replication of the genome as cells progress through S-phase. Here, the authors show that Mus81, an endonuclease involved in the response to DNA damage during replicative stress, also regulates the rate of DNA replication during normal growth.
- Haiqing Fu
- , Melvenia M. Martin
- & Mirit I. Aladjem
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Autoprocessing of neutrophil elastase near its active site reduces the efficiency of natural and synthetic elastase inhibitors
Elastase secreted by immune cells contributes to various lung diseases; however, elastase inhibitors have mostly failed in the clinic. Here, the authors discover a second, truncated form of elastase, which is the result of autocatalytic cleavage and is not well targeted by current synthetic elastase inhibitors.
- T. Dau
- , R. S. J. Sarker
- & D. E. Jenne
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Article
| Open AccessComprehensive identification of arginine methylation in primary T cells reveals regulatory roles in cell signalling
Arginine methylation is an important regulatory post-translational modification. Here, the authors present a new SILAC-based method—iMethyl-SILAC—that allows unambiguous identification of arginine-methylated peptide pairs by mass spectrometry and apply it to greatly expand the known T-cell arginine methylome.
- Vincent Geoghegan
- , Ailan Guo
- & Oreste Acuto
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ERK7 regulates ciliogenesis by phosphorylating the actin regulator CapZIP in cooperation with Dishevelled
The actin regulator CapZIP has been shown to regulate ciliogenesis in a phosphorylation-dependent manner. Miyatake et al.show that the atypical MAP kinase ERK7 promotes ciliogenesis by phophorylating CapZIP, and that interactions between both proteins and Dishevelled are required for CapZIP phosphorylation.
- Koichi Miyatake
- , Morioh Kusakabe
- & Eisuke Nishida
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Article
| Open AccessMolecular mechanisms of NET formation and degradation revealed by intravital imaging in the liver vasculature
Neutrophil extracellular traps (NETs) released by neutrophils trap pathogens but may also cause tissue damage. Here the authors show that during systemic Staphylococcus aureusinfection NETs anchoring to the vasculature are only partially DNase-sensitive, advocating for better anti-NET therapies.
- Elzbieta Kolaczkowska
- , Craig N. Jenne
- & Paul Kubes
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PRMT9 is a Type II methyltransferase that methylates the splicing factor SAP145
Protein arginine methylation is an abundant post-translational modification often associated with RNA-binding proteins. Here the authors show that the previously uncharacterized PRMT9 enzyme catalyses the symmetrical methylation of SAP145, which promotes its association with the SMN complex and regulates splicing.
- Yanzhong Yang
- , Andrea Hadjikyriacou
- & Mark T. Bedford
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ANKS6 is the critical activator of NEK8 kinase in embryonic situs determination and organ patterning
Protein kinase NEK8 is important for cilliary function, but the mechanism by which it acts is unknown. Czarnecki et al. identify the cilliary protein ANKS6 as a target and crucial activator of NEK8 and describe the importance of this protein interaction in embryonic development and organogenesis.
- Peter G. Czarnecki
- , George C. Gabriel
- & Jagesh V. Shah
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Stable metal-organic frameworks containing single-molecule traps for enzyme encapsulation
Enzymatic catalytic processes have great industrial potential, although their application is hampered by stability and reuse issues. Here, the authors report metal-organic frameworks with rationally designed single-molecule traps for enzyme encapsulation, and evaluate the activity of the confined enzymes.
- Dawei Feng
- , Tian-Fu Liu
- & Hong-Cai Zhou
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A mechanism-based inactivator of glycoside hydrolases involving formation of a transient non-classical carbocation
Mechanism-based enzyme inhibitors, useful as research probes, are typically based on a small number of structural motifs. Here, the authors report a mechanism-based inhibitor of galactosidases that functions by forming a carbocation within the active site, and subsequently alkylating a nucleophilic residue.
- Saswati Chakladar
- , Yi Wang
- & Andrew J. Bennet
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An antioxidant nanozyme that uncovers the cytoprotective potential of vanadia nanowires
It is known that some nanomaterials can exhibit enzyme-like activities, prompting interest in the novel applications this property may allow. Here, the authors show how vanadia nanowires possess glutathione peroxidase-like activity, and can effectively protect cells from oxidative damage.
- Amit A. Vernekar
- , Devanjan Sinha
- & Govindasamy Mugesh
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Structure-guided mutational analysis reveals the functional requirements for product specificity of DOT1 enzymes
DOT1A and DOT1B are African trypanosome homologues of the enzyme DOT1 methyltransferase, which is involved in the methylation of the histone H3K79. In this study, the authors identify specific residues that modulate the specificity of these enzymes for different forms of methylation.
- Gülcin Dindar
- , Andreas M. Anger
- & Christian J. Janzen
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Enzyme activity in liquid lipase melts as a step towards solvent-free biology at 150 °C
Enzymatic reactions typically occur in aqueous media or with hydrated enzymes. Here, the authors form fluid enzyme-polymer conjugates with sub-solvation levels of water, and demonstrate catalytic hydrolysis in the absence of a solvent at high temperatures.
- Alex P. S. Brogan
- , Kamendra P. Sharma
- & Stephen Mann
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Article
| Open AccessStructural basis for biomolecular recognition in overlapping binding sites in a diiron enzyme system
The ability of a protein to interact with multiple other proteins is an intriguing problem. Here, the authors use crystallography to show how a diiron hydroxylase achieves two distinct steps in the catalytic reaction, by using an overlapping binding site to recognize two different binding partners.
- Justin F. Acheson
- , Lucas J. Bailey
- & Brian G. Fox
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Out-of-frame start codons prevent translation of truncated nucleo-cytosolic cathepsin L in vivo
The lysosomal protease cathepsin L has been observed in compartments other than endosomes and lysosomes. Here the authors show using knock-in mice that nuclear localization of cathepsin L cannot be caused by N-terminal truncation of procathepsin L as previously hypothesized.
- Martina Tholen
- , Larissa E. Hillebrand
- & Thomas Reinheckel
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The fidelity of the ligation step determines how ends are resolved during nonhomologous end joining
DNA double strand breaks result in various types of damaged termini and are resolved by non-homologous end joining, but how cells coordinate the different steps that occur during repair is not clear. Here the authors show that a DNA ligase coordinates processing prior to the ligation step to limit errors.
- Crystal A. Waters
- , Natasha T. Strande
- & Dale A. Ramsden
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IP6K structure and the molecular determinants of catalytic specificity in an inositol phosphate kinase family
Inositol trisphosphate kinases (IP3Ks) and inositol hexakisphosphate kinases (IP6Ks) are involved in signalling by phosphorylating their specific targets. Here, Wang et al.report the crystal structure of a hybrid IP6K/IP3K enzyme, analyse the substrate orientations and propose an evolutionary trajectory for this kinase family.
- Huanchen Wang
- , Eugene F. DeRose
- & Stephen B. Shears
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Article
| Open AccessAmiA is a penicillin target enzyme with dual activity in the intracellular pathogen Chlamydia pneumoniae
Penicillin inhibits growth of chlamydial pathogens despite their lack of a conventional peptidoglycan cell wall. Here the authors report that the chlamydial amidase, AmiA, which can rescue cell division defects of an E. coli amiAmutant, has dual activity as a penicillin sensitive, lipid II-targetting carboxypeptidase.
- Anna Klöckner
- , Christian Otten
- & Beate Henrichfreise
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Structural basis for catalysis in a CDP-alcohol phosphotransferase
The transfer of a phosphate group from a CDP-linked donor to an acceptor alcohol is catalysed by CDP-alcohol phosphotransferases. Here, Sciara et al. report crystal structures of a CDP-alcohol phosphotransferase, define roles of conserved residues and propose a mechanism of action for this protein family.
- Giuliano Sciara
- , Oliver B. Clarke
- & Filippo Mancia
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Article
| Open AccessMolecular insights into the membrane-associated phosphatidylinositol 4-kinase IIα
Type II PI4-kinase dysfunction is associated with diseases including cancer and Alzheimer's disease; however, the development of specific modulators has been hampered by a lack of structural information. Zhou et al. present the crystal structure of PI4KIIα in its ADP-bound form, providing insight into its regulation.
- Qiangjun Zhou
- , Jiangmei Li
- & Chang Chen
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Article
| Open AccessThe structure and substrate specificity of human Cdk12/Cyclin K
Cyclin-dependent kinase 12 (Cdk12) phosphorylates the C-terminal domain (CTD) of RNA polymerase II to regulate transcription. Here, the authors solve the crystal structure of the Cdk12 kinase domain and show that Cdk12 has its highest activity on a CTD substrate that carries a serine 7 phosphorylation.
- Christian A. Bösken
- , Lucas Farnung
- & Matthias Geyer
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Visualizing autophosphorylation in histidine kinases
The phosphorylation of proteins is a common mechanism for signal transduction. Here, the authors present a structural analysis of a histidine kinase in the process of autophosphorylation, helping to elucidate the catalytic mechanism.
- Patricia Casino
- , Laura Miguel-Romero
- & Alberto Marina
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A sequence-specific DNA glycosylase mediates restriction-modification in Pyrococcus abyssi
Restriction enzymes are generally thought to act as sequence-specific endonucleases. Here Miyazono et al.demonstrate that one of these enzymes, R.PabI, is instead an adenine DNA glycosylase, expanding the known mechanisms by which a restriction-modification system can operate.
- Ken-ichi Miyazono
- , Yoshikazu Furuta
- & Masaru Tanokura
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Kinase fusions are frequent in Spitz tumours and spitzoid melanomas
Spitzoid neoplasms constitute a spectrum of melanocytic tumours, characterized by distinct clinical, pathological and genetic features. Here, Wiesner et al. show that kinase fusions represent the majority of oncogenic aberrations in spitzoid neoplasms and may serve as therapeutic targets for metastatic spitzoid melanoma.
- Thomas Wiesner
- , Jie He
- & Boris C. Bastian
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DNA repair choice defines a common pathway for recruitment of chromatin regulators
Chromatin regulators facilitate repair of DNA double-strand breaks in chromosomal DNA. The authors show that the recruitment of such chromatin regulators to DNA lesions is controlled by the choice of DNA repair pathway.
- Gwendolyn Bennett
- , Manolis Papamichos-Chronakis
- & Craig L. Peterson
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Characterization of salt-adapted secreted lignocellulolytic enzymes from the mangrove fungus Pestalotiopsis sp.
Fungi associated with the roots of mangroves are thought to turn-over significant quantities of organic matter including lignocellulose. Arfi et al. investigate the lignocellolytic potential of a fungal species isolated from mangrove roots and the adaptation of its enzymatic repertoire to a high salinity environment.
- Yonathan Arfi
- , Didier Chevret
- & Eric Record
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Article
| Open AccessTopoisomerase IIα promotes activation of RNA polymerase I transcription by facilitating pre-initiation complex formation
Topoisomerases facilitate the progress of elongating polymerases during transcription. Zomerdijk and colleagues now demonstrate an additional role for this enzyme; their data suggest that Top2 can cleave DNA inducing topological changes at the ribosomal DNA promoter, which assists de novoassembly of the RNA polymerase I pre-initiation complex.
- Swagat Ray
- , Tatiana Panova
- & Joost C. B. M. Zomerdijk
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Article
| Open AccessGreater efficiency of photosynthetic carbon fixation due to single amino-acid substitution
Phosphoenolpyruvate carboxylase, the key enzyme of C4 photosynthesis, evolved from an ancestral isoform in C3 plants and has a reduced feedback inhibition. Paulus et al.show that enhanced inhibitor tolerance of C4 phosphoenolpyruvate carboxylase is achieved by a single amino-acid exchange.
- Judith Katharina Paulus
- , Daniel Schlieper
- & Georg Groth
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Article
| Open AccessHuman CLPP reverts the longevity phenotype of a fungal ClpP deletion strain
The mitochondrial protease CLPP is found in most eukaryotic organisms but its biological role has been unclear. Here Osiewacz and colleagues show that deletion of CLPP extends lifespan of the filamentous fungus Podospora anserina, and that human and fungal CLPP are functionally conserved.
- Fabian Fischer
- , Andrea Weil
- & Heinz D. Osiewacz
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Article
| Open AccessIdentification and characterization of a human mitochondrial NAD kinase
Despite the central importance of NADP+ in mitochondrial energy metabolism, no NAD kinase has been found in human mitochondria to synthesize NADP+. These authors show C5orf33, a protein specific to animals and protists, to be the missing NAD kinase and demonstrate its mitochondrial localization and activity.
- Kazuto Ohashi
- , Shigeyuki Kawai
- & Kousaku Murata
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Diminishing returns and tradeoffs constrain the laboratory optimization of an enzyme
Enzymes are traditionally viewed as being highly specific for their substrates. Tokuriki et al.follow the accumulation of mutations during the laboratory evolution of a phosphotriesterase into an arylesterase, and postulate that many naturally occurring enzymes may not be optimal for their substrates.
- Nobuhiko Tokuriki
- , Colin J. Jackson
- & Dan S. Tawfik