Volume 8 Issue 2, February 2012

Volume 8 Issue 2

Photoisomerization of the visual pigment chromophore 11-cis-retinal is the first step of vision, and this event produces all-trans-retinal, whose delayed clearance from the retina is linked to retinal degeneration. Maeda et al. show that compounds containing a primary amine can protect a mouse disease model from light-induced retinal degeneration by forming a transient Schiff base with all-trans-retinal. Shown is staining of a vertebrate retina consisting of several layers of differentiated neural cells, including rod (red) and cone (green) photoreceptors. Cover art by Erin Dewalt, based on an image from Krzysztof Palczewski. Article, p170

Research Highlights

News and Views

  • News & Views |

    Patch-clamp fluorometry measurements of cAMP binding and channel opening combined with global kinetic fitting revealed that ligand binding to the tetrameric hyperpolarization-activated cyclic nucleotide–gated channel is favored at the second and fourth binding events.

    • Lei Zhou
  • News & Views |

    Mucopolysaccharidoses are inherited disorders in which inactivation of lysosomal enzymes results in accumulation of glycosaminoglycans within cells, causing tissue and organ dysfunction. A method to determine the unique end structures of the accumulated glycosaminoglycans offers a new way for diagnosis.

    • Lena Kjellén
  • News & Views |

    20(S)-hydroxycholesterol, a naturally occurring oxysterol, activates the Hedgehog signaling pathway by directly binding an allosteric site on Smoothened.

    • Hayley J Sharpe
    •  & Frederic J de Sauvage

Brief Communications

  • Brief Communication |

    Studies elucidating the role of p38α MAPK in diverse biological processes are limited by the lack of a specific inhibitor. Skepinone-L is a highly selective ATP-competitive inhibitor of p38 with excellent potency in vivo.

    • Solveigh C Koeberle
    • , Johannes Romir
    • , Stefan Fischer
    • , Andreas Koeberle
    • , Verena Schattel
    • , Wolfgang Albrecht
    • , Christian Grütter
    • , Oliver Werz
    • , Daniel Rauh
    • , Thilo Stehle
    •  & Stefan A Laufer
  • Brief Communication |

    A cheminformatics approach helps identify proteins such as GPCRs, ion channels and kinases that are targeted by small molecules that give phenotypes in a zebrafish behavioral assay.

    • Christian Laggner
    • , David Kokel
    • , Vincent Setola
    • , Alexandra Tolia
    • , Henry Lin
    • , John J Irwin
    • , Michael J Keiser
    • , Chung Yan J Cheung
    • , Daniel L Minor Jr
    • , Bryan L Roth
    • , Randall T Peterson
    •  & Brian K Shoichet

Articles

  • Article |

    Threading of a polypeptide chain is required for knotted proteins to adopt active conformations. A cell-free translation system in conjunction with pulse proteolysis to track folding of trefoil knotted proteins reveal that these knots form spontaneously, but GroEL–GroES enhances the rate of post-translational knot formation.

    • Anna L Mallam
    •  & Sophie E Jackson
  • Article |

    Polyketide synthases make use of a limited set of enzymes to create diverse natural products. The discovery that a ketosynthase homolog catalyzes ester bond formation instead of the typical Claisen condensation uncovers a previously unknown mechanism to generate chemical diversity.

    • Tom Bretschneider
    • , Georg Zocher
    • , Michelle Unger
    • , Kirstin Scherlach
    • , Thilo Stehle
    •  & Christian Hertweck
  • Article |

    The four subunits of the tetrameric voltage-sensitive HCN channel have different cAMP binding affinities, with the second and fourth binding events being positively cooperative and the third being negatively cooperative, suggesting a double-dimeric organization of the channel.

    • Jana Kusch
    • , Susanne Thon
    • , Eckhard Schulz
    • , Christoph Biskup
    • , Vasilica Nache
    • , Thomas Zimmer
    • , Reinhard Seifert
    • , Frank Schwede
    •  & Klaus Benndorf
  • Article |

    Compounds containing a primary amino group can protect against light-induced retinal degeneration in a mouse model of Stargardt’s disease and age-related retinal degeneration by forming a transient Schiff base with all-trans-retinal, lowering its intracellular concentration and preventing accumulation of lipofuscin chromophores in the eye.

    • Akiko Maeda
    • , Marcin Golczak
    • , Yu Chen
    • , Kiichiro Okano
    • , Hideo Kohno
    • , Satomi Shiose
    • , Kaede Ishikawa
    • , William Harte
    • , Grazyna Palczewska
    • , Tadao Maeda
    •  & Krzysztof Palczewski
  • Article |

    Natural product–inspired compounds are primed to interact with and manipulate biological processes, but obtaining these complex molecules poses synthetic challenges. The development of a 12-step, 1-pot cascade reaction leads to the 'centrocountins', tetrahydroindoloquinolizines that modulate mitosis by targeting the centrosome-associated proteins nucleophosmin and Crm1.

    • Heiko Dückert
    • , Verena Pries
    • , Vivek Khedkar
    • , Sascha Menninger
    • , Hanna Bruss
    • , Alexander W Bird
    • , Zoltan Maliga
    • , Andreas Brockmeyer
    • , Petra Janning
    • , Anthony Hyman
    • , Stefan Grimme
    • , Markus Schürmann
    • , Hans Preut
    • , Katja Hübel
    • , Slava Ziegler
    • , Kamal Kumar
    •  & Herbert Waldmann
  • Article |

    Screens of large compound libraries identify new small–molecule proteostasis regulators that, by enhancing the activity of the heat shock response factor HSF–1 and by activating other components of the proteostasis network, such as the antioxidant response or the unfolded protein response pathways, restore protein folding in multiple models of protein conformational diseases.

    • Barbara Calamini
    • , Maria Catarina Silva
    • , Franck Madoux
    • , Darren M Hutt
    • , Shilpi Khanna
    • , Monica A Chalfant
    • , S Adrian Saldanha
    • , Peter Hodder
    • , Bradley D Tait
    • , Dan Garza
    • , William E Balch
    •  & Richard I Morimoto
  • Article |

    Mucopolysaccharidoses are caused by a deficiency in GAG processing and can often be treated if the dysfunctional enzyme can be identified. A chemical derivatization strategy in combination with biochemical logic now yields a series of biomarkers that can be used to distinguish these disorders.

    • Roger Lawrence
    • , Jillian R Brown
    • , Kanar Al-Mafraji
    • , William C Lamanna
    • , James R Beitel
    • , Geert-Jan Boons
    • , Jeffrey D Esko
    •  & Brett E Crawford
  • Article |

    DNA repair proteins require efficient pathways to search for DNA damage lesions within a large genome. Kinetic trapping experiments define the rates of human uracil DNA glycosylase hopping and sliding along damaged DNA substrates and highlight the role of the phosphodiester backbone in DNA sliding.

    • Joseph D Schonhoft
    •  & James T Stivers
  • Article |

    20(S)-hydroxycholesterol binds to Smo at a site distinct from cyclopamine and activates signaling via an allosteric mechanism. A new alkyne oxysterol analog selectively captures Smo from membrane extracts and provides a new method for detecting protein-sterol interactions.

    • Sigrid Nachtergaele
    • , Laurel K Mydock
    • , Kathiresan Krishnan
    • , Jayan Rammohan
    • , Paul H Schlesinger
    • , Douglas F Covey
    •  & Rajat Rohatgi