• Commentary |

    Wayne Hendrickson discusses the consortium efforts and developments in methodology that in recent years have allowed unprecedented advances in atomic-structure determination of membrane proteins.

    • Wayne A Hendrickson
  • Commentary |

    Telomerase is a nucleoprotein complex of a reverse transcriptase and an RNA that binds complementary telomeric-repeat DNA sequences and directs their extension. In this Commentary, the authors propose how hairpin structures formed by telomeric DNA repeats promote addition of telomerase repeats and why telomere sequences are evolutionarily conserved despite the problems that they pose to DNA replication.

    • Wei Yang
    •  & Young-Sam Lee
  • Commentary |

    Recent advances in RNA-sequencing technologies have led to the discovery of thousands of previously unannotated noncoding transcripts, including many long noncoding RNAs (lncRNAs) whose functions remain largely unknown. Here, the authors discuss considerations and best practices when identifying and annotating lncRNAs that should aid their functional and mechanistic exploration.

    • John S Mattick
    •  & John L Rinn
  • Commentary |

    The natural versatility of RNA makes it an ideal substrate for bioengineering. Its structural properties and predictable base-pairing permit its use as molecular scaffold, and its ability to interact with nucleic acids, proteins and small molecules confers a regulatory potential that can be harvested to design RNA regulators in diverse contexts.

    • Cameron Myhrvold
    •  & Pamela A Silver
  • Commentary |

    Cellular fate is determined by transcriptional networks and epigenetic states. In addition to protein factors, noncoding RNAs (ncRNAs), particularly microRNAs and long ncRNAs, are able to remodel transcriptional circuits and reshape epigenetic landscapes. This Commentary highlights the emerging roles of these ncRNAs in cellular reprogramming, transdifferentiation and organ regeneration.

    • Mo Li
    •  & Juan Carlos Izpisua Belmonte
  • Commentary
    | Open Access

    We report the outcomes of the discussion initiated at the workshop entitled A 3D Cellular Context for the Macromolecular World and propose how data from emerging three-dimensional (3D) cellular imaging techniques—such as electron tomography, 3D scanning electron microscopy and soft X-ray tomography—should be archived, curated, validated and disseminated, to enable their interpretation and reuse by the biomedical community.

    • Ardan Patwardhan
    • , Alun Ashton
    • , Robert Brandt
    • , Sarah Butcher
    • , Raffaella Carzaniga
    • , Wah Chiu
    • , Lucy Collinson
    • , Pascal Doux
    • , Elizabeth Duke
    • , Mark H Ellisman
    • , Erik Franken
    • , Kay Grünewald
    • , Jean-Karim Heriche
    • , Abraham Koster
    • , Werner Kühlbrandt
    • , Ingvar Lagerstedt
    • , Carolyn Larabell
    • , Catherine L Lawson
    • , Helen R Saibil
    • , Eduardo Sanz-García
    • , Sriram Subramaniam
    • , Paul Verkade
    • , Jason R Swedlow
    •  & Gerard J Kleywegt
  • Commentary |

    The past decade has witnessed an explosion in the identification of ubiquitin-ligase complexes as the missing receptors for important small-molecule hormones regulating plant growth and development. These breakthroughs were initiated by genetic approaches, with structural analysis providing mechanistic insights into how hormone perception and signaling are coupled to protein ubiquitination. Although there are still many unknowns, plants have imparted valuable lessons about the pharmacology of ubiquitin modification.

    • Nitzan Shabek
    •  & Ning Zheng
  • Commentary |

    Protein homeostasis is essential for cellular function, organismal growth and viability. Damaged and aggregated proteins are turned over by two major proteolytic routes of the cellular quality-control pathways: the ubiquitin-proteasome system and autophagy. For both these pathways, ubiquitination provides the recognition signal for substrate selection. This Commentary discusses how ubiquitin-dependent proteolytic pathways are coordinated with stress- and aging-induced signals.

    • Éva Kevei
    •  & Thorsten Hoppe
  • Commentary |

    The immune system must operate in an effective, precise and safe manner to defend against diverse pathogens while avoiding attacking the body itself and commensal bacteria. Inflammatory pathways mediated by NOD-like, Toll-like, RIG-I–like and tumor-necrosis-factor receptor families are tightly regulated by ubiquitination, especially by Lys63-linked and linear polyubiquitin chains. Here we discuss the human ubiquitin-mediated inflammatory signaling system, emphasizing the interactions and activities whose coordination ensures timely, accurate regulation of inflammatory responses.

    • Jacob E Corn
    •  & Domagoj Vucic
  • Commentary |

    Given the recent successes in determining membrane-protein structures, we explore the tractability of determining representatives for the entire human membrane proteome. This proteome contains 2,925 unique integral α-helical transmembrane-domain sequences that cluster into 1,201 families sharing more than 25% sequence identity. Structures of 100 optimally selected targets would increase the fraction of modelable human α-helical transmembrane domains from 26% to 58%, providing structure and function information not otherwise available.

    • Ursula Pieper
    • , Avner Schlessinger
    • , Edda Kloppmann
    • , Geoffrey A Chang
    • , James J Chou
    • , Mark E Dumont
    • , Brian G Fox
    • , Petra Fromme
    • , Wayne A Hendrickson
    • , Michael G Malkowski
    • , Douglas C Rees
    • , David L Stokes
    • , Michael H B Stowell
    • , Michael C Wiener
    • , Burkhard Rost
    • , Robert M Stroud
    • , Raymond C Stevens
    •  & Andrej Sali
  • Commentary
    | Open Access

    This report describes the outcomes of the Data Management Challenges in 3D Electron Microscopy workshop. Key topics discussed include data models, validation and raw-data archiving. The meeting participants agreed that the EMDataBank should take the lead in addressing these issues, and concrete action points were agreed upon that will have a substantial impact on the accessibility of three-dimensional EM data in biology and medicine.

    • Ardan Patwardhan
    • , José-Maria Carazo
    • , Bridget Carragher
    • , Richard Henderson
    • , J Bernard Heymann
    • , Emma Hill
    • , Grant J Jensen
    • , Ingvar Lagerstedt
    • , Catherine L Lawson
    • , Steven J Ludtke
    • , David Mastronarde
    • , William J Moore
    • , Alan Roseman
    • , Peter Rosenthal
    • , Carlos-Oscar S Sorzano
    • , Eduardo Sanz-García
    • , Sjors H W Scheres
    • , Sriram Subramaniam
    • , John Westbrook
    • , Martyn Winn
    • , Jason R Swedlow
    •  & Gerard J Kleywegt
  • Commentary |

    Until recently, few potent and broadly neutralizing HIV-specific antibodies had been identified, but recent findings have inspired optimism that an effective HIV vaccine can finally be developed. Here we review these studies, which used state-of-the-art high-throughput techniques to collectively describe hundreds of new potent and broad HIV-neutralizing antibodies isolated from HIV-infected individuals.

    • Susan Moir
    • , Angela Malaspina
    •  & Anthony S Fauci
  • Commentary |

    How does a transcription factor select a specific DNA response element given the presence of degenerate sequences? To date, this question has largely been viewed from the standpoint of DNA sequence variability and transcription factor binding affinity under steady-state conditions. Here we propose that to address this problem, it is also necessary to account for fluctuating cellular conditions. These lead to dynamic changes in the ensemble of protein (and DNA) conformational states via allosteric effects.

    • Yongping Pan
    • , Chung-Jung Tsai
    • , Buyong Ma
    •  & Ruth Nussinov
  • Commentary |

    The WD40 protein WDR5 is a core subunit of the human MLL and SET1 (hCOMPASS) histone H3 Lys4 (H3K4) methyltransferase complexes. Although initial studies suggested that WDR5 interacts with methylated H3K4 to catalyze Lys4 trimethylation, recent work has revealed that it binds an arginine-bearing motif in MLL1, promoting complex assembly and activity. These findings suggest that WDR5 functions as a peptidyl arginine–recognition factor that facilitates the assembly of hCOMPASS and other chromatin-modifying complexes.

    • Raymond C Trievel
    •  & Ali Shilatifard
  • Commentary |

    Eukaryotes transcribe much of their genomes, but little is known about the fidelity of transcriptional initiation by RNA polymerase II in vivo. I suggest that 90% of Pol II initiation events in yeast represent transcriptional noise, and that the specificity of initiation is comparable to that of DNA-binding proteins and other biological processes. This emphasizes the need to develop criteria that distinguish transcriptional noise from transcription with a biological function.

    • Kevin Struhl
  • Commentary |

    The tails of the four core histones are exposed on the nucleosome surface, where they are subject to a variety of enzyme-catalyzed, post-translational modifications. Modifications, singly or in combination, provide a source of information that can be used for signal transduction during ongoing processes, such as transcription, or as heritable epigenetic marks. A nomenclature is presented that allows patterns of histone modification to be clearly and unambiguously specified and that should facilitate discussion of their functional roles.

    • Bryan M Turner
  • Commentary |

    The research in biology has been transformed by the products of interdisciplinary research. Here we explore why it is challenging for universities to bring biologists together with engineers, physicists and computer scientists for productive collaboration, and we evaluate alternative solutions. In particular, we describe how the new Janelia Farm Research Campus of Howard Hughes Medical Institute aims to provide a home for creative scientists from different disciplines to attack major biomedical research problems.

    • Thomas R Cech
    •  & Gerald M Rubin
  • Commentary |

    Fashions prevail in science as in all human affairs. In recent years, biochemistry has become less fashionable, but there is no doubt that the discipline is important for the full understanding of biology.

    • Arthur Kornberg
  • Commentary |

    Two camps continue to evolve in the field of structural biology—a 'systems-oriented' camp, which studies proteins or complexes carefully one system at a time, and a 'discovery-oriented' one, which studies proteins of entire families, pathways or genomes. The end goals of both camps are the same: to decipher the atomic-resolution structures and mechanisms of biological macromolecules and understand them in the context of the living cell.

    • Raymond C Stevens
  • Commentary |

    Structural genomics efforts are already producing a quarter of all 'new' macromolecular structures (<30% sequence identity to previously solved structures) and are stimulating development of systematic and automated approaches to structure determination. The thousands of new structures likely to be determined and the technologies and infrastructure likely to be developed over the next decade will benefit all biologists.

    • Thomas C Terwilliger
  • Commentary |

    We know the basic principles of protein, RNA and DNA structure, and we have atomic coordinates of many proteins and RNAs. Structural biology must now expand the range of length and timescales on which we can represent the molecular reality of a cell. Structural molecular biology and structural cell biology must merge into a single discipline, and we must establish a lively intellectual complementarity with the nascent 'systems biology' of the cell.

    • Stephen C Harrison
  • Commentary |

    Twenty-first century research in the life sciences is becoming an increasingly interdisciplinary endeavor where teams of scientists use tools and insights from a variety of fields to solve complex biological problems. By and large, our educational system has not kept up with these changes. How can science education and the life sciences curriculum better reflect the way students will do science when they leave the hallowed halls of academia?

    • Andrew L Feig
  • Commentary |

    • Caroline M. Groft
    • , Roland Beckmann
    • , Andrej Sali
    •  & Stephen K. Burley
  • Commentary |

    • Michelle F. Browner
    • , Sarah A. Gillmor
    •  & Robert Fletterick