Volume 19 Issue 7, July 2012

Volume 19 Issue 7

Mammalian dioxygenase ALKBH2 searches the genome for alkylation lesions and mediates their direct repair. He and colleagues now show that ALKBH2 probes the stability of base pairs to find DNA damage, and its oxidative demethylation mechanism ensures that only cognate lesions are processed, similar to the mechanism of gear wheels for a safe lock. Image by John A. Shaw from Shutterstock. pp 671–676

News and Views

  • News & Views |

    RNA silencing is a sequence-specific gene regulation system conserved in eukaryotes, at the core of which lies the Argonaute protein family. Crystallographic studies of eukaryotic Argonaute proteins now reveal remarkably similar overall structures to their prokaryotic homologs while shedding new light on the fundamental relationship between their conformational dynamics and sophisticated strategies to silence specific targets.

    • Hiroshi M Sasaki
    •  & Yukihide Tomari
  • News & Views |

    New structural analyses suggest two different models for poly(ADP-ribose) polymerase 1 (PARP1) activation by single- and double-strand DNA breaks, providing evidence for PARP1 activation in cis and in trans.

    • Nicolas Coquelle
    •  & J N Mark Glover
  • News & Views |

    HIV-1 avoids the immune detection of infected cells by preventing class I molecules of the major histocompatibility complex (MHC-I) bound to viral peptides from reaching the cell surface. A new structure shows how Nef turns MHC-I from a noncargo into a cargo for the clathrin adaptor AP-1, thus directing MHC-I to the lysosome instead of the plasma membrane.

    • James H Hurley
    •  & Juan S Bonifacino

Research Highlights

Articles

  • Article |

    Noncoding RNAs have been implicated in targeting the repressive polycomb complex PRC2 to specific genomic sites. In vivo cross-linking studies now reveal a number of intronic RNA sequences capable of binding the EZH2 subunit of PRC2 in human cancer cells and downregulating transcription of the SMYD3 histone methyltransferase gene, among others. Overexpression of an EZH2-interacting RNA was found to counteract tumorigenicity.

    • Sònia Guil
    • , Marta Soler
    • , Anna Portela
    • , Jordi Carrère
    • , Elena Fonalleras
    • , Antonio Gómez
    • , Alberto Villanueva
    •  & Manel Esteller
  • Article |

    Mammalian dioxygenase ALKBH2 mediates direct oxidative repair of alkylation DNA lesions. Structural, biochemical and computational approaches are now used to reveal that ALKBH2 probes base pair stability by inserting a hydrophobic hairpin motif into the DNA duplex and does not need a damage-checking site, in contrast to DNA glycosylases.

    • Chengqi Yi
    • , Baoen Chen
    • , Bo Qi
    • , Wen Zhang
    • , Guifang Jia
    • , Liang Zhang
    • , Charles J Li
    • , Aaron R Dinner
    • , Cai-Guang Yang
    •  & Chuan He
  • Article |

    Leucyl-tRNA synthetase (LeuRS) synthesizes and then proofreads leucyl-tRNALeu for accurate protein synthesis. Structural analysis of Escherichia coli LeuRS reveals that the editing domain unexpectedly stabilizes the tRNA during aminoacylation and that translocation of the leucyl-tRNALeu from the aminoacylation site to the editing site requires correlated movements of several LeuRS domains.

    • Andrés Palencia
    • , Thibaut Crépin
    • , Michael T Vu
    • , Tommie L Lincecum Jr
    • , Susan A Martinis
    •  & Stephen Cusack
  • Article |

    PARP1 is activated by sensing DNA damage, forming ADP-ribose chains that recruit DNA repair and chromatin remodeling factors. PARP1 recognizes DNA damage through its DNA-binding domain, which contains two zinc-finger regions (ZnF1 and ZnF2). The crystal structure of human PARP1-DBD bound to a DNA break reveals a dimeric arrangement, in which ZnF1 from one monomer interacts with ZnF2 from the other monomer, to recognize the DNA strand break.

    • Ammar A E Ali
    • , Gyula Timinszky
    • , Raquel Arribas-Bosacoma
    • , Marek Kozlowski
    • , Paul O Hassa
    • , Markus Hassler
    • , Andreas G Ladurner
    • , Laurence H Pearl
    •  & Antony W Oliver
  • Article |

    The Mre11–Rad50–Nbs1 (MRN) complex plays a central role in DNA damage signaling. The crystal structures of the Schizosaccharomyces pombe Mre11 catalytic domain in its apo form and in complex with a fragment of Nbs1 are now reported. Along with functional analyses, the work provides insight into checkpoint signaling and ATM activation as well as a framework to understand disease-related mutations.

    • Christian B Schiller
    • , Katja Lammens
    • , Ilaria Guerini
    • , Britta Coordes
    • , Heidi Feldmann
    • , Florian Schlauderer
    • , Carolin Möckel
    • , Alexandra Schele
    • , Katja Strässer
    • , Stephen P Jackson
    •  & Karl-Peter Hopfner
  • Article |

    The HIV-1 Nef protein associates with the cytoplasmic domain of class I MHC and with the μ1 subunit of clathin adaptor protein complex I, rerouting MHC I to the endolysosomal degradation pathway. The molecular mechanism for this effect is now revealed by the crystal structure of Nef together with MHC I and a domain from μ1.

    • Xiaofei Jia
    • , Rajendra Singh
    • , Stefanie Homann
    • , Haitao Yang
    • , John Guatelli
    •  & Yong Xiong
  • Article |

    Keratins form heterodimers that assemble into intermediate filaments. The structure of a central coiled-coil region formed between keratins 5 and 14 provides a new understanding of intermediate-filament architecture and assembly. Cellular data suggest a role for disulfide bridges in filament organization.

    • Chang-Hun Lee
    • , Min-Sung Kim
    • , Byung Min Chung
    • , Daniel J Leahy
    •  & Pierre A Coulombe

Brief Communications

  • Brief Communication |

    AMP-activated protein kinase (AMPK) has a central role in sensing cellular metabolic levels. Crystal structures of the AMPK core in the presence of AMP or ATP suggest that the third nucleotide-binding site in the γ subunit is important for allosteric regulation of kinase activity.

    • Lei Chen
    • , Jue Wang
    • , Yuan-Yuan Zhang
    • , S Frank Yan
    • , Dietbert Neumann
    • , Uwe Schlattner
    • , Zhi-Xin Wang
    •  & Jia-Wei Wu
  • Brief Communication |

    The process of pre-mRNA splicing involves connecting two exons while releasing the intron as a transient branched RNA, or as a lariat. Deep-sequencing analysis has enabled the first large-scale identification of branch points in human pre-mRNA transcripts in vivo, onto which the distribution of splicing factor binding was mapped.

    • Allison J Taggart
    • , Alec M DeSimone
    • , Janice S Shih
    • , Madeleine E Filloux
    •  & William G Fairbrother
  • Brief Communication |

    The crystal structures of human STING in the apo and c-di-GMP–bound states, supported by mutagenesis and biochemical data, reveal that c-di-GMP binds to preformed dimeric STING. c-di-GMP prolongs STING phosphorylation in vitro, which may contribute to downstream IFN signaling. These findings aid in understanding the innate immune response to bacterial infection.

    • Chang Shu
    • , Guanghui Yi
    • , Tylan Watts
    • , C Cheng Kao
    •  & Pingwei Li
  • Brief Communication |

    STING is an important component of the innate immune system involved in the direct response to the bacterial second messenger c-di-GMP. The structures of human STING in the presence and absence of c-di-GMP show how recognition of c-di-GMP is achieved by dimeric STING, providing a basis for future studies investigating signal transduction mechanisms.

    • Guijun Shang
    • , Deyu Zhu
    • , Ning Li
    • , Junbing Zhang
    • , Chunyuan Zhu
    • , Defen Lu
    • , Cuilan Liu
    • , Qian Yu
    • , Yanyu Zhao
    • , Sujuan Xu
    •  & Lichuan Gu
  • Brief Communication |

    STING is an ER-resident membrane protein that triggers cytokine production upon detection of the bacterial second messenger c-di-GMP. The structures of the cytosolic domain of STING and the complex it forms with c-di-GMP lay the groundwork for understanding STING function.

    • Yi-He Huang
    • , Xiang-Yu Liu
    • , Xiao-Xia Du
    • , Zheng-Fan Jiang
    •  & Xiao-Dong Su

Technical Report

  • Technical Report |

    Tryptophan scanning is now used to characterize transient intermediate states in the folding pathway of a protein. By following the intrinsic fluorescence of tryptophan residues introduced at different solvent-exposed positions of model protein ubiquitin, the authors characterize a late folding intermediate.

    • Alexis Vallée-Bélisle
    •  & Stephen W Michnick