Post-translational modifications articles within Nature

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  • Letter |

    OTULIN, which removes ubiquitin chains deposited by LUBAC, promotes LUBAC activity by preventing its auto-ubiquitination, thereby supporting normal mouse embryo development and preventing pro-inflammatory cell death in adult mice.

    • Klaus Heger
    • , Katherine E. Wickliffe
    •  & Vishva M. Dixit

  • Letter |

    Structural mass spectrometry of full-length human parkin and a structure of the activated parkin core reveal large-scale domain rearrangements involved in activation of parkin by PINK1.

    • Christina Gladkova
    • , Sarah L. Maslen
    •  & David Komander

  • Letter |

    The X-ray structure of the integral membrane protein isoprenylcysteine carboxyl methyltransferase suggests mechanisms by which it recognizes both water-soluble and membrane-bound reactants to catalyze the methylation of RAS and other CAAX proteins at the membrane-cytosol interface.

    • Melinda M. Diver
    • , Leanne Pedi
    •  & Stephen B. Long

  • Article |

    Stabilization of a transient protein kinase–substrate complex using a nanobody provides molecular details about how the Parkinson’s disease-linked protein kinase PINK1 phosphorylates ubiquitin, and suggests new pharmacological strategies.

    • Alexander F. Schubert
    • , Christina Gladkova
    •  & David Komander

  • Letter |

    The development of selective ubiquitin-specific protease-7 (USP7) inhibitors GNE-6640 and GNE-6776, which induce tumour cell death and reveal differential kinetics of Lys-48 and Lys-63-linked ubiquitin chain depolymerization by USP7.

    • Lorna Kategaya
    • , Paola Di Lello
    •  & Ingrid E. Wertz

  • Article |

    This paper reports the identification of a new cereblon-modulating agent, CC-885, which targets the translation termination factor GSPT1 and demonstrates anti-tumour activity in patient-derived tumour cells; the crystal structure of the cereblon–DDB1–GSPT1–CC-885 complex reveals a common motif for cereblon-substrate recruitment.

    • Mary E. Matyskiela
    • , Gang Lu
    •  & Philip P. Chamberlain

  • Article |

    Much of the intracellular protein degradation in eukaryotes is controlled by cullin–RING ubiquitin ligases (CRLs), a vast class of enzymes which are regulated by the COP9 signalosome (CSN); structural characterization of CSN–N8CRL4A complexes by cryo-electron microscopy reveals an induced-fit mechanism of CSN activation triggered only by catalytically activated CRLs without bound substrate, explaining how CSN acts as a global regulator of CRLs.

    • Simone Cavadini
    • , Eric S. Fischer
    •  & Nicolas H. Thomä

  • Letter |

    Thalidomide and its derivative lenalidomide bind the CRL4CRBN E3 ubiquitin ligase and target protein substrates for degradation; structural and functional data determined here show that casein kinase 1α and the lymphoid transcription factor Ikaros, the efficacy targets of lenalidomide in two different blood cancers, interact with the CRBN–lenalidomide interface through a β-hairpin destruction motif.

    • Georg Petzold
    • , Eric S. Fischer
    •  & Nicolas H. Thomä

  • Letter |

    The first structure of fully active HOIP of the RBR family of RING-type E3 ligases in its transfer complex with an E2~ubiquitin conjugate provides insights into its mechanism of action, including the ideal alignment of the E2 and E3 catalytic centres for ubiquitin transfer and the allosteric regulation of the RBR family.

    • Bernhard C. Lechtenberg
    • , Akhil Rajput
    •  & Stefan J. Riedl

  • Letter |

    Expression of the tumour suppressor PTEN in disseminated primary tumour cells is lost after tumour cells metastasize to the brain, with downregulation instigated by microRNAs from astrocytes, which are transferred from cell to cell by exosomes; these findings reveal the dynamic nature of metastatic cancer cells when adapting to a new tissue environment.

    • Lin Zhang
    • , Siyuan Zhang
    •  & Dihua Yu

  • Letter |

    This study shows that a vertebrate-specific ubiquitin ligase modulates neural crest specification in Xenopus development and human embryonic stem-cell differentiation; a proteomics approach reveals that the CUL3KBTBD8 ligase modulates translation by targeting the modulators of ribosomes production NOLC1 and its paralogue TCOF1, which is mutated in a neural-crest-associated syndrome.

    • Achim Werner
    • , Shintaro Iwasaki
    •  & Michael Rape

  • Article |

    A ChIP-seq analysis of the DNA-binding properties of mutant gain-of-function p53 protein compared to wild-type p53 reveals the gain-of-function proteins bind to and activate a distinct set of genes including chromatin modifying enzymes such as the histone methyltransferase MLL; small molecular inhibitors of MLL function may represent a new target for cancers with mutant p53.

    • Jiajun Zhu
    • , Morgan A. Sammons
    •  & Shelley L. Berger

  • Article |

    The PINK1 ubiquitin kinase is shown to recruit the two autophagy receptors NDP52 and OPTN to mitochondria to activate mitophagy directly, independently of the ubiquitin ligase parkin; once recruited to mitochondria, NDP52 and OPTN recruit autophagy initiation components, and parkin may amplify the phospho-ubiquitin signal generated by PINK1, resulting in robust autophagy induction.

    • Michael Lazarou
    • , Danielle A. Sliter
    •  & Richard J. Youle

  • Letter |

    This study provides insights into conformational changes that lead to phospho-ubiquitin-induced PARKIN activation and how PARKIN is recruited to phospho-ubiquitin chains on mitochondria; the crystal structure of PARKIN in complex with phospho-ubiquitin also indicates that the pocket within PARKIN where phospho-ubiquitin binds carries amino acid residues that are mutated in patients with autosomal-recessive juvenile Parkinsonism.

    • Tobias Wauer
    • , Michal Simicek
    •  & David Komander

  • Letter |

    The interplay of histone acetylation and RNA polymerase II activity is investigated using fluorescence microscopy; acetylation of H3 at Lys 27 enhances the recruitment of a transcriptional activator and accelerates the transition of RNA polymerase II from initiation to elongation, thus indicating that histone acetylation has a causal effect on two distinct steps in transcription activation.

    • Timothy J. Stasevich
    • , Yoko Hayashi-Takanaka
    •  & Hiroshi Kimura

  • Letter |

    SMYD3 is a methyltransferase overexpressed in several human tumours; here methylation of the MAP3K2 kinase by SMYD3 is shown to be critical for Ras-induced tumour development in mouse models and human tumour cells, showing an unexpected role for methylation in a kinase signalling pathway and revealing a candidate therapeutic target.

    • Pawel K. Mazur
    • , Nicolas Reynoird
    •  & Or Gozani

  • Letter |

    RIG-I protein recognizes viral duplex RNA with a 5′-triphosphate group, activating innate immune responses; a crystal structure of its tetrameric CARD signalling domain reveals that non-covalently linked ubiquitin chains stabilize the tetramer in a ‘lock-washer’ structure that serves as a signalling platform for the recruitment and activation of MAVS.

    • Alys Peisley
    • , Bin Wu
    •  & Sun Hur

  • Letter |

    This study finds a direct correlation between LARGE-glycan extension on dystroglycan and the protein’s capacity for extracellular matrix ligands; in regenerating mouse muscle, short LARGE-glycan polysaccharides cause various defects, including muscle dysfunction and a predisposition to dystrophy, and in muscular dystrophy patients, increased clinical severity of disease corresponds to shorter LARGE-glycans.

    • Matthew M. Goddeeris
    • , Biming Wu
    •  & Kevin P. Campbell

  • Letter |

    Several death-domain-containing proteins are directly inactivated by the enteropathogenic Escherichia coli type III secretion system effector NleB; NleB functions as an N-acetylglucosamine transferase that modifies a conserved death domain arginine residue, blocking the receptor–adapter interaction.

    • Shan Li
    • , Li Zhang
    •  & Feng Shao

  • Article |

    This study shows that 53BP1 recruitment to sites of DNA damage involves dual recognition of H4K20me2 and H2AK15 histone ubiquitination; the ubiquitin mark and the surrounding epitope on H2A are read by a region of 53BP1 designated the ubiquitination-dependent recruitment motif.

    • Amélie Fradet-Turcotte
    • , Marella D. Canny
    •  & Daniel Durocher

  • News & Views |

    Necrosis is associated with various diseases, yet it is arguably the least-understood form of programmed cell death. It emerges that a sirtuin protein regulates one form of necrosis through a deacetylation reaction. See Article p.199

    • Wen Zhou
    •  & Junying Yuan

  • Article |

    Here it is shown that the NAD-dependent deacetylase SIRT2 is an essential component of necrosis, and that mouse hearts that do not contain SIRT2 or that are treated with a pharmacological inhibitor of SIRT2 are largely protected from ischaemic injury.

    • Nisha Narayan
    • , In Hye Lee
    •  & Toren Finkel

  • Article |

    N6-methyladenosine (m6A) is the most prevalent internal modification in messenger RNA; here the human and mouse m6A modification landscape is presented in a transcriptome-wide manner, providing insights into this epigenetic modification.

    • Dan Dominissini
    • , Sharon Moshitch-Moshkovitz
    •  & Gideon Rechavi

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