Proteins articles within Nature

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  • Article |

    Cardiac hypertrophy is associated with a decrease in expression of the adult isoform of the molecular motor myosin heavy chain (α-MHC) and the induction of expression of its fetal isoform (β-MHC). Here the authors reveal the mechanism regulating this switch in expression, which impairs heart function. Cardiac stress in adult hearts reactivates the developmental chromatin-modifying complex Brg1/BAF, which interacts with histone deacetylase and poly (ADP ribose) polymerase to induce a pathological α-MHC-to-β-MHC shift.

    • Calvin T. Hang
    • , Jin Yang
    •  & Ching-Pin Chang

  • Letter |

    Circadian rhythms control many physiological functions. During periods of feeding, pancreatic islets secrete insulin to maintain glucose homeostasis — a rhythmic process that is disturbed in people with diabetes. These authors show that pancreatic islets contain their own clock: they have self-sustained circadian oscillations of CLOCK and BMAL1 genes and proteins, which are vital for the regulation of circadian rhythms. Without this clock, a cascade of cellular failure and pathology initiates the onset of diabetes mellitus.

    • Biliana Marcheva
    • , Kathryn Moynihan Ramsey
    •  & Joseph Bass

  • Technology Feature |

    Proteins in cell membranes are notoriously hard to crystallize, but new techniques give scientists the means to map them. Monya Baker scouts out the tools for cracking the structure of membrane proteins.

    • Monya Baker

  • 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 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

  • 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

  • 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 |

    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 |

    GABAB receptors are the G-protein-coupled receptors for γ-aminobutyric acid (GABA), the main inhibitory neurotransmitter in the brain. Here, functional proteomics is used to show that GABAB receptors in the brain are complexes of GABAB1, GABAB2 and members of a subfamily of KCTD proteins. The KCTD proteins increase the potency of agonists and markedly alter the G-protein signalling of the receptors, suggesting that they determine the pharmacology and kinetics of the receptor response.

    • Jochen Schwenk
    • , Michaela Metz
    •  & Bernhard Bettler

  • 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 |

    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 |

    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 |

    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 |

    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

  • Letter |

    Fibrillar deposits of tau protein (neurofibrillary tangles) are thought to cause neuronal death in patients with Alzheimer's disease, and tau-related frontotemporal dementia. Here, however, the opposite has been found: the activation of executioner caspase enzymes occurs first, preceding tangle formation by hours to days. Tangle-bearing neurons seem to be long-lived, indicating that tangles might be 'off pathway' to acute neuronal death.

    • Alix de Calignon
    • , Leora M. Fox
    •  & Bradley T. Hyman

  • Letter |

    Zebrafish are able to replace lost heart muscle efficiently, and are used as a model to understand why natural heart regeneration — after a heart attack, for instance — is blocked in mammals. Here, and in an accompanying paper, genetic fate-mapping approaches reveal which cell population contributes prominently to cardiac muscle regeneration after an injury approximating myocardial infarction. The results show that cardiac muscle regenerates through activation and expansion of existing cardiomyocytes, without involving a stem-cell population.

    • Kazu Kikuchi
    • , Jennifer E. Holdway
    •  & Kenneth D. Poss

  • Article |

    Cellular senescence — an irreversible cell-cycle arrest — has been implicated in suppressing tumour formation or growth. A new cellular signalling pathway that drives senescence has now been identified. This pathway does not involve most known mediators of senescence, and instead signals via the proteins Atf4, p27 and p21. Inactivating the proto-oncogene Skp2 in the context of oncogenic signalling can induce senescence through this new pathway, indicating that drugs that target Skp2 might be useful in cancer treatment.

    • Hui-Kuan Lin
    • , Zhenbang Chen
    •  & Pier Paolo Pandolfi

  • Letter |

    Variation in the regulation of gene transcription between individuals is thought to be a major cause of phenotypic diversity. Here, individual differences in the binding of transcription-factor proteins are studied. A well-known transcription factor in the yeast pheromone pathway is used as an example, and the underlying genetic loci responsible for variation in its binding are mapped. The study reveals new insights into the mechanisms of gene regulation, and new regulators of the yeast pheromone pathway.

    • Wei Zheng
    • , Hongyu Zhao
    •  & Michael Snyder

  • Letter |

    During Arabidopsis embryogenesis, a single cell is specified to become the founder cell of the root meristem — the hypophysis — in response to signals from adjacent cells. Hypophysis specification requires an auxin-responsive transcription factor, MONOPTEROS (MP), which promotes transport of auxin from the embryo to the hypophysis precursor. Here, MP target genes are identified and the means by which they mediate root formation is shown.

    • Alexandra Schlereth
    • , Barbara Möller
    •  & Dolf Weijers

  • Letter |

    During fasting SIRT3 is induced in liver and brown adipose tissue. One of SIRT3's substrates is shown to be long–chain acyl co-enzyme A dehydrogenase (LCAD). Without SIRT3 LCAD becomes hyperacetylated, which diminishes its activity, and reduces fatty acid oxidation. Mice without SIRT3 have all the hallmarks of fatty acid oxidation disorders during fasting, including reduced ATP levels and intolerance to cold. Thus, acetylation is a novel regulatory mechanism for fatty acid oxidation.

    • Matthew D. Hirschey
    • , Tadahiro Shimazu
    •  & Eric Verdin

  • Letter |

    During development in Arabidopsis plants, populations of shoot stem cells and root stem cells are established at the embryo's apical and basal poles, respectively. PLETHORA genes are master regulators of root fate, but the regulators of shoot fate were unknown. Here, CLASS III HOMEODOMAIN-LEUCINE ZIPPER genes are identified as master regulators of apical/shoot fate, and are shown to be sufficient to convert the embryonic root pole into a second shoot pole.

    • Zachery R. Smith
    •  & Jeff A. Long

  • News & Views |

    Although sphingolipids are vital cellular components, the path to their production is paved with toxic intermediates. Orm proteins allow cells to form these lipids without killing themselves in the process.

    • Fikadu G. Tafesse
    •  & Joost C. M. Holthuis

  • Letter |

    The RAS–RAF signalling pathway is an attractive target for drug development in oncology, and several RAF inhibitors are being tested in clinical trials. Here and in an accompanying paper, RAF inhibitors are shown to have opposing roles, functioning as either inhibitors or activators of RAF depending on the cellular context and mutational status of RAF. The mechanistic basis for these opposing roles is dissected. The results have implications for the clinical use of these inhibitors and for the design of kinase inhibitors.

    • Poulikos I. Poulikakos
    • , Chao Zhang
    •  & Neal Rosen

  • Article |

    The post-translational modification of cellular proteins by ubiquitin (Ub) and ubiquitin-like (Ubl) proteins — such as SUMO — regulates a broad array of cellular processes. E1 enzymes activate Ub and Ubl in two steps, by carboxy-terminal adenylation and thioester bond formation to a catalytic cysteine, but the structural basis for the intermediates remains unknown. Crystal structures for SUMO E1 in complex with SUMO adenylate and tetrahedral intermediate analogues are now reported and analysed.

    • Shaun K. Olsen
    • , Allan D. Capili
    •  & Christopher D. Lima

  • News & Views |

    Researchers have met the challenge of capturing transient states of the SUMO E1 activating enzyme. Their pictures show radically different crystal structures for two of the steps in this enzyme's activity.

    • Brenda A. Schulman
    •  & Arthur L. Haas

  • News & Views |

    When environmental temperatures rise, plants seek help from their core molecular mechanisms to adapt. The chromatin protein H2A.Z, which regulates gene expression, is one such rescue molecule.

    • Roger B. Deal
    •  & Steven Henikoff

  • Letter |

    Endogenous retroviruses (ERVs) are widely dispersed in mammalian genomes, and are silenced in somatic cells by DNA methylation. Here, an ERV silencing pathway independent of DNA methylation is shown to operate in embryonic stem cells. The pathway involves the histone H3K9 methyltransferase ESET and might be important for ERV silencing during the stages in embryogenesis when DNA methylation is reprogrammed.

    • Toshiyuki Matsui
    • , Danny Leung
    •  & Yoichi Shinkai

  • Article |

    Pancreatic β-cells release insulin, which controls energy homeostasis in vertebrates, and its lack causes diabetes mellitus. The transcription factor neurogenin 3 (Neurog3) initiates differentiation of β-cells and other islet cell types from pancreatic endoderm; here, the transcription factor Rfx6 is shown to direct islet cell differentiation downstream of Neurog3 in mice and humans. This may be useful in efforts to generate β-cells for patients with diabetes.

    • Stuart B. Smith
    • , Hui-Qi Qu
    •  & Michael S. German

  • Letter |

    Ca2+ channels and calmodulin (CaM) are two prominent hubs of biological signalling networks, affecting functions such as cardiac excitability and gene transcription. The prevailing view has been that the ultrastrong affinity of channels for the Ca2+-free form of calmodulin (apoCaM) ensures their saturation with CaM and yields a form of concentration independence between Ca2+ channels and CaM. Here, however, significant exceptions to this autonomy are shown to exist.

    • Xiaodong Liu
    • , Philemon S. Yang
    •  & David T. Yue

  • Letter |

    The transcription factor Tbx3 is shown to significantly improve the quality of induced pluripotent stem (iPS) cells. Tbx3 binding sites in embryonic stem cells are present in genes involved in pluripotency and reprogramming factors. Furthermore, there are intrinsic qualitative differences in iPS cells generated by different methods in terms of their pluripotency, thus highlighting the need to rigorously characterize iPS cells beyond in vitro studies.

    • Jianyong Han
    • , Ping Yuan
    •  & Bing Lim

  • Letter |

    Chronic myeloid leukaemia is caused by a BCR-ABL fusion, a constitutively active tyrosine kinase that, it is believed, leads to suppression of the forkhead O transcription factors (FOXO). Although the use of the tyrosine kinase inhibitor imatinib is a breakthrough for CML therapy, imatinib does not deplete the leukaemia-initiating cells (LICs) that drive the recurrence of CML. Foxo3a is now shown to have an essential role in the maintenance of CML LICs in a mouse model.

    • Kazuhito Naka
    • , Takayuki Hoshii
    •  & Atsushi Hirao

  • Letter |

    Heterozygous mutations in the gene encoding CHD7, an ATP-dependent chromatin-remodelling protein, result in CHARGE syndrome — a disorder characterized by malformations of the craniofacial structures, peripheral nervous system, ears, eyes and heart. In humans and Xenopus, CHD7 is now shown to be essential for the formation of multipotent migratory neural crest and for activating the transcriptional circuitry of the neural crest; shedding light on the pathoembryology of CHARGE syndrome.

    • Ruchi Bajpai
    • , Denise A. Chen
    •  & Joanna Wysocka

  • News & Views |

    Damaged lysosomes, the principal degradative organelles, can kill a cell. A stress-induced protein controls lysosome stability, providing a potential target to treat lysosome-related diseases and cancer.

    • Ibolya Horváth
    •  & László Vígh

  • Article |

    Mouse and human fibroblasts can be reprogrammed to a pluripotent state with a combination of four transcription factors. Here, mature differentiated cells are directed, via a combination of a few transcription factors (distinct from those described for generating iPS cells), to form functional neurons in vitro, without having to revert the fibroblasts to an embryonic state.

    • Thomas Vierbuchen
    • , Austin Ostermeier
    •  & Marius Wernig

  • Letter |

    Although cyclin D1 is frequently overexpressed in human cancers, the full range of its functions in normal development and oncogenesis is unclear. Here, tagged cyclin D1 knock-in mouse strains are developed to allow a search for cyclin D1-binding proteins in different mouse organs using high-throughput mass spectrometry. The results show that, in addition to its established cell cycle roles, cyclin D1 has an in vivo transcriptional function in mouse development.

    • Frédéric Bienvenu
    • , Siwanon Jirawatnotai
    •  & Piotr Sicinski

  • Letter |

    Antimicrobial peptides (AMPs) are an important class of immune effector molecules which fight pathogen infections. AMP induction in Drosophila is regulated through the activation of the Toll and immune deficiency pathways; it is now shown that AMP activation can be achieved independently of these pathways by the transcription factor FOXO. In non-infected animals, AMP genes are activated in response to nuclear FOXO activity when induced by starvation.

    • Thomas Becker
    • , Gerrit Loch
    •  & Michael Hoch

  • Letter |

    Rho is a general transcription termination factor in bacteria, but the mechanism by which it disrupts the RNA polymerase (RNAP) elongation complex is unknown. Here, Rho is shown to bind tightly to the RNAP throughout the transcription cycle, with the formation of the RNAP–Rho complex being crucial for termination. Furthermore, RNAP is proposed to have an active role in Rho termination through an allosteric mechanism.

    • Vitaly Epshtein
    • , Dipak Dutta
    •  & Evgeny Nudler

  • News & Views |

    The key enzyme in photosynthesis, Rubisco, is a relic of a bygone age. The ability to assemble Rubisco in the test tube offers the prospect of genetically manipulating the enzyme to make it fit for the modern world.

    • R. John Ellis

  • Letter |

    Phenotypic robustness in the face of genetic and environmental perturbations — known as canalization — relies on buffering mechanisms. Hsp90 chaperone machinery has been proposed to be an evolutionarily conserved buffering mechanism of phenotypic variance. Here, an additional, perhaps alternative, mechanism whereby Hsp90 influences phenotypic variation is proposed; Hsp90 mutations can generate new variation by transposon-mediated mutagenesis.

    • Valeria Specchia
    • , Lucia Piacentini
    •  & Maria P. Bozzetti

  • Article |

    Although Archaea encode proteasomes highly related to those of eukaryotes, archaeal ubiquitin-like proteins are less conserved and not known to function in protein conjugation, complicating our understanding of the origins of ubiquitination. Two small archaeal modifier proteins, SAMP1 and SAMP2, structurally similar to ubiquitin, are now reported to form protein conjugates in the archaeon Haloferax volcanii.

    • Matthew A. Humbard
    • , Hugo V. Miranda
    •  & Julie A. Maupin-Furlow

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