Biochemistry articles within Nature

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  • Letter |

    The association of microRNAs with Argonaute proteins (AGOs) yields complexes regulating gene expression. Although bacterial and archaeal miRNAs show no sequence preference at their 5′ ends, eukaryotic miRNAs tend to have a 5′ U or A. Here the structure of the human AGO2 MID domain complexed with ribonucleotide monophosphates is solved, revealing specific interaction of UMP and AMP with a loop that discriminates against CMP or GMP, and explaining the observed preference.

    • Filipp Frank
    • , Nahum Sonenberg
    •  & Bhushan Nagar

  • Letter |

    The Escherichia coli isocitrate dehydrogenase kinase/phosphatase (AceK) is a bifunctional enzyme that can phosphorylate or dephosphorylate isocitrate dehydrogenase (ICDH) to either inactivate or activate it in response to environmental changes. Now the structures of AceK and the AceK–ICDH complex have been solved, revealing the conformational changes that occur when AceK changes from a kinase to a phosphatase and vice versa.

    • Jimin Zheng
    •  & Zongchao Jia

  • Letter |

    Proteins often comprise domains that can be distinguished as relatively separate regions in the three-dimensional structure. Communication between these domains is important for catalysis, regulation and folding, but how they communicate is largely unclear. Here, single-molecule optical tweezers were used to pull on a protein while monitoring the energetics of unfolding and refolding events in disparate regions. By comparing topological variations of the same protein, new rules of cooperation between domains were derived.

    • Elizabeth A. Shank
    • , Ciro Cecconi
    •  & Carlos Bustamante

  • Letter |

    Toxoplasma gondii is an opportunistic human pathogen that secretes organelles called micronemes during infection. This is important for parasite motility, host-cell invasion and egress. It is now shown that the secretion of micronemes is dependent on the T. gondii calcium-dependent protein kinase 1. This kinase is not found in the parasite's mammalian hosts, and might represent a valid drug target.

    • Sebastian Lourido
    • , Joel Shuman
    •  & L. David Sibley

  • Letter |

    The initiation of protein synthesis requires the eukaryotic translation initiation factor (eIF) 2, which uses energy from the hydrolysis of GTP. Another factor, eIF5, accelerates the GTP-hydrolysing activity of eIF2. Here, two other roles for eIF5 have been defined. One involves stabilizing GDP, the product of GTP hydrolysis, on eIF2. In its other role, eIF5 works with phosphorylated eIF2 to inhibit the guanine-nucleotide exchange factor eIF2B. These results clarify our understanding of how the initiation of translation is regulated.

    • Martin D. Jennings
    •  & Graham D. Pavitt

  • News & Views |

    In plant roots, patterning of two types of water-conducting xylem tissue is determined by a signalling system that involves the reciprocal dance of a mobile transcription factor and mobile microRNAs.

    • Ben Scheres

  • Letter |

    The need to maintain the structural and functional integrity of an evolving protein limits the range of acceptable amino-acid substitutions — but to what extent does this constrain how far homologous protein sequences can diverge? Here, sequence divergence data are used to explore the limits of protein evolution, and to conclude that ancient proteins are continuing to diverge from one another, indicating that the protein sequence universe is slowly expanding.

    • Inna S. Povolotskaya
    •  & Fyodor A. Kondrashov

  • Article |

    Toll-like receptors (TLRs) are crucial to innate immunity. Activation of these proteins, and of receptors for the pro-inflammatory cytokines IL-1 and IL-18, leads to the recruitment of adaptor proteins such as MyD88. These in turn interact with further proteins such as IRAK2 and IRAK4. The crystal structure of the MyD88–IRAK2–IRAK4 death domain complex is now reported, explaining how these three proteins cooperate in TLR/IL-1R signalling.

    • Su-Chang Lin
    • , Yu-Chih Lo
    •  & Hao Wu

  • Letter |

    Staphylococcal superantigens can lead to toxic shock syndrome. They are encoded on pathogenicity islands and with the aid of helper phages can be excised and packaged into highly transmissable phage particles. Here it is shown that a specific, non-essential helper phage protein is responsible for derepression of the pathogenicity island, thereby providing the mechanism for the first step of its mobilization.

    • María Ángeles Tormo-Más
    • , Ignacio Mir
    •  & José R. Penadés

  • Letter |

    Spider silk proteins are remarkably soluble when stored at high concentration and yet can be converted to extremely sturdy fibres, through unknown molecular mechanisms. Here, the structure of the evolutionarily conserved carboxy-terminal domain of a silk protein is presented. The results provide evidence that the structural state of this domain is essential for controlled switching between the storage and assembly forms of silk proteins. Such molecular switches might see application in the design of versatile fibrous materials.

    • Franz Hagn
    • , Lukas Eisoldt
    •  & Horst Kessler

  • Letter |

    Traditional robots need to store internal representations of their goals and environment, and to coordinate sensing and the movement of components required in response. Individual molecules are limited in their ability to store complex information, but robotic behaviour can still be realized — as has now been shown with DNA walkers, which can carry out a sequence of actions such as 'start', 'follow', 'turn' and 'stop' that are programmed into the DNA landscape on which the walkers move.

    • Kyle Lund
    • , Anthony J. Manzo
    •  & Hao Yan

  • Letter |

    Many new functional materials and devices could be made if it were possible to rationally combine nanometre-scale particles into larger structures. An assembly line operating on the nanometre scale has now been demonstrated. It uses a DNA origami tile as a framework and track for the assembly process, three distinct DNA machines attached to the tile as programmable cargo-donating devices, and a DNA walker to generate the target product by moving along the track and collecting cargo from those devices that are switched on.

    • Hongzhou Gu
    • , Jie Chao
    •  & Nadrian C. Seeman

  • Letter |

    Spider silk proteins are remarkably soluble when stored at high concentration and yet can be converted to extremely sturdy fibres, through unknown molecular mechanisms. Here, the X-ray structure of the amino-terminal domain of a silk protein is presented, revealing how evolutionarily conserved polar surfaces might control self-assembly as the pH is lowered along the spider's silk extrusion duct. Such a mechanism might be applicable to the design of versatile fibrous materials.

    • Glareh Askarieh
    • , My Hedhammar
    •  & Stefan D. Knight

  • Article |

    Neurotransmitter:Na+ symporters (NSS) remove neurotransmitters from the synapse in a reuptake process that is driven by the Na+ gradient. Here, single-molecule fluorescence imaging assays have been combined with molecular dynamics simulations to probe the conformational changes that are associated with substrate binding and transport by a prokaryotic NSS homologue, LeuT. The findings are interpreted in the context of an allosteric mechanism that couples ion and substrate binding to transport.

    • Yongfang Zhao
    • , Daniel Terry
    •  & Jonathan A. Javitch

  • News & Views |

    Membrane transporter proteins switch between conformational states to move substrates across membranes. The transition between these states can now be studied using single-molecule experiments.

    • Nathan K. Karpowich
    •  & Da-Neng Wang

  • Letter |

    Copper is an essential trace element for eukaryotes and most prokaryotes, but it has toxic side effects, so the levels of intracellular free copper must be limited. Mass spectrometry has now been used to measure the apparent Cu(I)-binding affinities of a representative set of intracellular copper proteins involved in redox catalysis, in copper trafficking to and within different cellular compartments, and in copper storage. The results provide the thermodynamic basis for the kinetic processes that lead to the distribution of cellular copper.

    • Lucia Banci
    • , Ivano Bertini
    •  & Peep Palumaa

  • Letter |

    The enzyme inositol polyphosphate phosphatase 4A (INPP4A) removes phosphate groups from phosphatidylinositol-3,4-bisphosphate, a key cellular lipid. Here, a crucial role for INPP4A in maintaining the integrity of the brain is described. Mice that lack this enzyme suffer from neurodegeneration in the striatum of the brain, as well as severe involuntary movements. When present, INPP4A protects neurons from a particular type of cell death.

    • Junko Sasaki
    • , Satoshi Kofuji
    •  & Takehiko Sasaki

  • Letter |

    The ability of plants to 'green' in the dark is attributed to the activity of the dark-operative protochlorophyllide oxidoreductase (DPOR). This enzyme catalyses the stereospecific reduction of the C17≡C18 double bond of protochlorophyllide to form chlorophyllide a, the direct precursor of chlorophyll a. The X-ray crystal structure of the catalytic component of DPOR has now been solved. A chemical mechanism is proposed by which the reduction of the double bond may occur.

    • Norifumi Muraki
    • , Jiro Nomata
    •  & Yuichi Fujita

  • News & Views |

    Controversy has raged over the identity of the metal cofactor of membrane-bound methane monooxygenase, a methane-oxidizing enzyme. A study suggests that the answer is a cluster of two copper ions.

    • J. Martin Bollinger Jr

  • News & Views |

    Diverse messenger RNAs, and thus proteins, can be generated from a single piece of DNA. A computational approach is helping to uncover complex combinatorial rules by which specific gene instructions are selected.

    • J. Ramón Tejedor
    •  & Juan Valcárcel

  • Letter |

    Polycomb group (PcG) proteins are transcriptional repressors that modify chromatin and regulate important developmental genes. One PcG-associated, chromatin-modifying activity is an enzyme that ubiquitinates histone H2A of chromatin. Here, a fruitfly PcG complex that is associated with H2A deubiquitination, and thereby with gene repression, is identified. PcG-mediated gene silencing might thus involve a dynamic balance between ubiquitination and deubiquitination of H2A.

    • Johanna C. Scheuermann
    • , Andrés Gaytán de Ayala Alonso
    •  & Jürg Müller

  • Letter |

    Dynamin is a protein that catalyses the scission of clathrin-coated pits at the plasma membrane. The mechanisms of dynamin-catalysed scission remain poorly understood. Here, the structure of the stalk region of human MxA, a dynamin-like protein, is presented. A structural model of MxA oligomerization and stimulated GTP hydrolysis is put forward that has functional implications for all members of the dynamin family.

    • Song Gao
    • , Alexander von der Malsburg
    •  & Oliver Daumke

  • Article |

    Dynamin is a protein that catalyses the fission of clathrin-coated endocytic vesicles from cellular membranes. To carry out fission, it must hydrolyse GTP. The mechanism by which it does so is unknown, although it does require dynamin's GTPase effector domain (GED). Here, the structure of a minimal GTPase–GED fusion protein constructed from human dynamin 1 is presented. The structure reveals the catalytic machinery and provides new insight into the mechanisms underlying dynamin-catalysed membrane fission.

    • Joshua S. Chappie
    • , Sharmistha Acharya
    •  & Fred Dyda

  • Article |

    MicroRNAs, which regulate gene expression, are transcribed as longer sequences that are processed to produce the mature form. Two nuclease enzymes, Drosha and Dicer, are known to act sequentially to trim the microRNA to size. Here, however, a subset of microRNAs that includes miR-451, important for erythropoiesis, is found to be processed independently of Dicer. Rather, the Argonaute protein — part of the complex that aligns microRNA and messenger RNA — carries out the secondary cleavage.

    • Sihem Cheloufi
    • , Camila O. Dos Santos
    •  & Gregory J. Hannon

  • Letter |

    Hydrogen metabolism is facilitated by the activity of three hydrogenase enzymes. The catalytic core of the [FeFe]-hydrogenase (HydA), called the H-cluster, exists as a [4Fe4S] subcluster linked to a modified 2Fe subcluster. Here, Chlamydomonas reinhardtii HydA was expressed in a genetic background that did not contain the other hydrogenase biosynthetic genes. The structure of this HydA was then solved, revealing the stepwise manner by which the H-cluster is synthesized, and offering insight into how HydA might have evolved.

    • David W. Mulder
    • , Eric S. Boyd
    •  & John W. Peters

  • Letter |

    Before mating, a yeast cell must detect a partner cell that is close enough and expresses sufficiently large amounts of a sex pheromone. The mating decision is an all-or-none, switch-like response to pheromone concentration. It is now shown that this decision involves the competition of one kinase and one phosphatase enzyme for multiple phosphorylation sites on a 'scaffold' protein. The results should prompt a re-evaluation of the role of related signalling molecules that have been implicated in cancer.

    • Mohan K. Malleshaiah
    • , Vahid Shahrezaei
    •  & Stephen W. Michnick

  • Letter |

    Most human gene promoters are embedded within CpG islands that lack DNA methylation and coincide with sites at which histone H3 lysine 4 is trimethylated (H3K4me3 sites). Here, a zinc-finger protein, Cfp1, is found to be associated with non-methylated CpG islands and H3K4me3 sites throughout the genome in the mouse brain. A primary function of non-methylated CpG islands might be to genetically determine the local chromatin modification state by interaction with Cfp1 and perhaps other CpG-binding proteins.

    • John P. Thomson
    • , Peter J. Skene
    •  & Adrian Bird

  • Letter |

    Most agents that generate breaks in DNA leave 'dirty ends' that cannot be joined immediately; instead, intervening steps are required to restore the integrity of nucleotides at the break. Here it is shown that the non-homologous end joining pathway requires a 5′-dRP/AP lyase activity to remove abasic sites at double-strand breaks. Surprisingly, this activity is catalysed by the Ku70 protein, which, together with its partner Ku86, had been thought only to recognize broken DNA ends and to recruit other factors that process ends.

    • Steven A. Roberts
    • , Natasha Strande
    •  & Dale A. Ramsden

  • Letter |

    The ovarian hormones oestrogen and progesterone increase breast cancer risk but the cellular mechanisms are unclear. Here it is shown that the size of the mammary stem cell pool in mice is regulated by steroid hormone signalling, although these cells lack the receptors for oestrogen and progesterone. The augmented pool could lead to clonal expansion of a mutated cell, possibly accounting for the increased incidence of breast cancer associated with pregnancy.

    • Marie-Liesse Asselin-Labat
    • , François Vaillant
    •  & Jane E. Visvader

  • Letter |

    One of the roles of the human gut microbiota is to break down nutrients using bacterial enzymes that are lacking from the human genome. It is now shown that the gut microbiota of Japanese, but not American, individuals contains porphyranases, enzymes that digest sulphated polysaccharides which are present in the marine environment only. These findings indicate that diet can select for gene content of the human microbiota.

    • Jan-Hendrik Hehemann
    • , Gaëlle Correc
    •  & Gurvan Michel

  • News Feature |

    Almost every human protein has segments that can form amyloids, the sticky aggregates known for their role in disease. Yet cells have evolved some elaborate defences, finds Jim Schnabel.

    • Jim Schnabel

  • Letter |

    The fat mass and obesity-associated (FTO) gene has been associated with increased body weight. The FTO protein has DNA/RNA demethylase activity. Here, the crystal structure of human FTO in complex with the mononucleotide 3-methylthymidine is presented. The structure provides a basis for understanding the substrate specificity of FTO, and should serve as a foundation for the design of FTO inhibitors.

    • Zhifu Han
    • , Tianhui Niu
    •  & Jijie Chai

  • Letter |

    Nascent secretory or membrane proteins contain an amino-terminal signal peptide that mediates their targeting to the plasma membrane (in prokaryotes) or endoplasmic reticulum (in eukaryotes). This peptide is recognized by the signal recognition particle (SRP). A universally conserved component of the SRP is known as SRP54 (Ffh in bacteria). Here, the crystal structure of Sulfolobus solfataricus SRP54 fused to a signal peptide is presented, revealing how the signal peptide is recognized by SRP54.

    • Claudia Y. Janda
    • , Jade Li
    •  & Kiyoshi Nagai

  • Letter |

    Animals must detect water in their environment to stay alive, but the molecular basis for water detection has been unclear. Here the essential mediators of water-sensing and drinking in fruitflies have been identified: an ion channel of the degenerin/epithelial sodium channel family, and the sensory neurons that make it.

    • Peter Cameron
    • , Makoto Hiroi
    •  & Kristin Scott

  • Brief Communications Arising |

    • Julia Fischer
    • , Linda Koch
    •  & Ulrich Rüther

  • Letter |

    Rhodospsin is a G-protein-coupled receptor that is responsible for vision in dim light. Light isomerizes the protein's retinal chromophore and triggers concerted movements of several transmembrane helices. Here, an approach involving mutant rhodopsins and infrared spectroscopy enabled changes in the electrostatic environment to be seen as rhodopsin proceeded along its activation pathway. Early conformational changes were observed that precede the well-known larger movements of the transmembrane helices.

    • Shixin Ye
    • , Ekaterina Zaitseva
    •  & Reiner Vogel

  • Letter |

    Interleukin-17-producing helper T (TH17) cells are a distinct T-cell subset characterized by its role in autoimmune disease. Here it is shown that the development of TH17 cells requires the transcription factor IκBζ, as well as nuclear receptors of the ROR family. Mice lacking IκBζ have a defect in TH17 development and are resistant to the induction of experimental autoimmune encephalomyelitis. The study points to some new potential molecular targets for drugs to treat autoimmune disease.

    • Kazuo Okamoto
    • , Yoshiko Iwai
    •  & Hiroshi Takayanagi

  • Letter |

    During atherosclerosis, crystals of cholesterol accumulate in atherosclerotic plaques. But are they a consequence or a cause of the inflammation associated with the disease? Here it is shown that small cholesterol crystals appear early in the development of atherosclerosis, and that they act as an endogenous danger signal, causing inflammation by activating the NLRP3 inflammasome pathway. Cholesterol crystals thus seem to be an early cause, rather than a late consequence, of inflammation.

    • Peter Duewell
    • , Hajime Kono
    •  & Eicke Latz

  • Article |

    Adiponectin is a protein with anti-diabetic properties; its levels are decreased in obesity, insulin resistance and type 2 diabetes. It is shown here that mice with a muscle-specific disruption of adiponectin receptor 1 (AdipoR1) are insulin resistant and less able to endure exercise. The pathway downstream of receptor activation is delineated; the findings suggest that the decreased levels of adiponectin and AdipoR1 seen in obesity may have causal roles in the mitochondrial dysfunction and insulin resistance seen in diabetes.

    • Masato Iwabu
    • , Toshimasa Yamauchi
    •  & Takashi Kadowaki

  • Letter |

    In plants, the hormone jasmonoyl-isoleucine (JA-Ile) regulates growth, development and defence against pathogens. Proteins of the JAZ family repress JA-Ile-dependent gene expression, but the mechanism has been unclear. Here, an adaptor protein, NINJA, has been identified, which recruits co-repressor proteins that are known to mediate auxin-responsive gene expression as well. Hence these co-repressors are part of general repression complexes that are recruited to several different signalling pathways.

    • Laurens Pauwels
    • , Gemma Fernández Barbero
    •  & Alain Goossens

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