Journal Articles

  • Telling stories
    [Feb 2015]

    Nature -

    Telling stories

    Nature 518, 7538 (2015). doi:10.1038/518137a

    The UK Research Excellence Framework’s focus on impact is a useful reminder of all the ways that science can help society — both economically and by other means.

    Categories: Journal Articles
  • Spot the difference
    [Feb 2015]

    Nature -

    Spot the difference

    Nature 518, 7538 (2015). doi:10.1038/518137b

    The US measles outbreak highlights why most states should reconsider their vaccination rules.

    Categories: Journal Articles
  • Darwin’s iconic finches join genome club
    [Feb 2015]

    Nature -

    Darwin’s iconic finches join genome club

    Nature 518, 7538 (2015). http://www.nature.com/doifinder/10.1038/518147a

    Author: Geoff Marsh

    Scientists pinpoint genes behind famous beak variations.

    Categories: Journal Articles
  • Measles by the numbers: A race to eradication
    [Feb 2015]

    Nature -

    Measles by the numbers: A race to eradication

    Nature 518, 7538 (2015). http://www.nature.com/doifinder/10.1038/518148a

    Author: Declan Butler

    The US media are abuzz after an outbreak of measles in Disneyland but the disease will keep on popping up until it is wiped out worldwide.

    Categories: Journal Articles
  • Impact of UK research revealed in 7,000 case studies
    [Feb 2015]

    Nature -

    Impact of UK research revealed in 7,000 case studies

    Nature 518, 7538 (2015). http://www.nature.com/doifinder/10.1038/518150a

    Author: Richard Van Noorden

    Language analysis reflects how  projects succeeded in unique assessment.

    Categories: Journal Articles
  • Mesoscopic Segregation of Excitation and Inhibition in a Brain Network Model
    [Feb 2015]

    by Daniel Malagarriga, Alessandro E. P. Villa, Jordi Garcia-Ojalvo, Antonio J. Pons

    Neurons in the brain are known to operate under a careful balance of excitation and inhibition, which maintains neural microcircuits within the proper operational range. How this balance is played out at the mesoscopic level of neuronal populations is, however, less clear. In order to address this issue, here we use a coupled neural mass model to study computationally the dynamics of a network of cortical macrocolumns operating in a partially synchronized, irregular regime. The topology of the network is heterogeneous, with a few of the nodes acting as connector hubs while the rest are relatively poorly connected. Our results show that in this type of mesoscopic network excitation and inhibition spontaneously segregate, with some columns acting mainly in an excitatory manner while some others have predominantly an inhibitory effect on their neighbors. We characterize the conditions under which this segregation arises, and relate the character of the different columns with their topological role within the network. In particular, we show that the connector hubs are preferentially inhibitory, the more so the larger the node's connectivity. These results suggest a potential mesoscale organization of the excitation-inhibition balance in brain networks.
    Categories: Journal Articles
  • Highly Selective Pd-Catalyzed Intermolecular Fluorosulfonylation of Styrenes
    [Feb 2015]

    Journal of the American Chemical SocietyDOI: 10.1021/ja5131676
    Categories: Journal Articles
  • Editorial Board
    [Feb 2015]

    Publication date: 27 February 2015
    Source:Journal of Molecular Biology, Volume 427, Issue 4









    Categories: Journal Articles
  • Contents List
    [Feb 2015]

    Publication date: 27 February 2015
    Source:Journal of Molecular Biology, Volume 427, Issue 4









    Categories: Journal Articles
  • Titin and Obscurin: Giants Holding Hands and Discovery of a New Ig Domain Subset
    [Feb 2015]

    Publication date: 27 February 2015
    Source:Journal of Molecular Biology, Volume 427, Issue 4

    Author(s): Guy M. Benian , Olga Mayans







    Categories: Journal Articles
  • The Sum Is More Than The Parts: Crystal And Solution Data Reveal That The PIDDosome Core Complex Is a Dynamic Assembly
    [Feb 2015]

    Publication date: 27 February 2015
    Source:Journal of Molecular Biology, Volume 427, Issue 4

    Author(s): Remco Sprangers







    Categories: Journal Articles
  • The Crystal Structure of the Human Titin:Obscurin Complex Reveals a Conserved yet Specific Muscle M-Band Zipper Module
    [Feb 2015]

    Publication date: 27 February 2015
    Source:Journal of Molecular Biology, Volume 427, Issue 4

    Author(s): Stefano Pernigo , Atsushi Fukuzawa , Alessandro Pandini , Mark Holt , Jens Kleinjung , Mathias Gautel , Roberto A. Steiner

    M10 is the most C-terminal immunoglobulin (Ig) domain of the giant protein titin and a frequent target of disease-linked mutations. Currently, it is the only known muscle Ig domain able to interact with two alternative ligands—obscurin and obscurin-like-1 (Obsl1)—in different sarcomeric subregions. Obscurin and Obsl1 use their homologous N-terminal Ig domain (O1 in obscurin and OL1 in Obsl1) to bind M10 in a mutually exclusive manner. We present here the X-ray structure of the human titin:obscurin M10:O1 complex extending our previous work on the M10:OL1 interaction. Similar to M10:OL1, the M10:O1 complex displays a chevron-shaped antiparallel Ig–Ig architecture held together by a conserved molecular interface, which we validated by isothermal titration calorimetry and sorting experiments in neonatal rat cardiomyocytes. O1, although structurally related to OL1 and M10, both members of the intermediate set (I-set) Ig family, presents an intriguing switch of its βA′ strand. This leads to structural differences between the complexes, particularly for the “open side” of the chevron-shaped assembly. A bioinformatics analysis reveals that the βA′-switch observed for O1 is rare and that it is involved in mediating protein–protein interactions. Molecular dynamics simulations also suggest that this topological alteration substantially increases local flexibility compared to the conventional I-set Ig domains. The O1/OL1 Ig domains are candidate discriminatory structural modules potentially directing the binding of specific additional partners at the M-band. Cellular sorting experiments in neonatal rat cardiomyocytes are consistent with the view that the titin:obscurin/Obsl1 complexes might be a platform for higher-order interactions.
    Graphical abstract




    Categories: Journal Articles
  • Flexible Stoichiometry and Asymmetry of the PIDDosome Core Complex by Heteronuclear NMR Spectroscopy and Mass Spectrometry
    [Feb 2015]

    Publication date: 27 February 2015
    Source:Journal of Molecular Biology, Volume 427, Issue 4

    Author(s): Lily A. Nematollahi , Acely Garza-Garcia , Chérine Bechara , Diego Esposito , Nina Morgner , Carol V. Robinson , Paul C. Driscoll

    Homotypic death domain (DD)–DD interactions are important in the assembly of oligomeric signaling complexes such as the PIDDosome that acts as a platform for activation of caspase-2-dependent apoptotic signaling. The structure of the PIDDosome core complex exhibits an asymmetric three-layered arrangement containing five PIDD-DDs in one layer, five RAIDD-DDs in a second layer and an additional two RAIDD-DDs. We addressed complex formation between PIDD-DD and RAIDD-DD in solution using heteronuclear nuclear magnetic resonance (NMR) spectroscopy, nanoflow electrospray ionization mass spectrometry and size-exclusion chromatography with multi-angle light scattering. The DDs assemble into complexes displaying molecular masses in the range 130–158kDa and RAIDD-DD:PIDD-DD stoichiometries of 5:5, 6:5 and 7:5. These data suggest that the crystal structure is representative of only the heaviest species in solution and that two RAIDD-DDs are loosely attached to the 5:5 core. Two-dimensional 1H,15N-NMR experiments exhibited signal loss upon complexation consistent with the formation of high-molecular-weight species. 13C-Methyl-transverse relaxation optimized spectroscopy measurements of the PIDDosome core exhibit signs of differential line broadening, cross-peak splitting and chemical shift heterogeneity that reflect the presence of non-equivalent sites at interfaces within an asymmetric complex. Experiments using a mutant RAIDD-DD that forms a monodisperse 5:5 complex with PIDD-DD show that the spectroscopic signature derives from the quasi- but non-exact equivalent environments of each DD. Since this characteristic was previously demonstrated for the complex between the DDs of CD95 and FADD, the NMR data for this system are consistent with the formation of a structure homologous to the PIDDosome core.
    Graphical abstract




    Categories: Journal Articles
  • Bactobolin A Binds to a Site on the 70S Ribosome Distinct from Previously Seen Antibiotics
    [Feb 2015]

    Publication date: 27 February 2015
    Source:Journal of Molecular Biology, Volume 427, Issue 4

    Author(s): Alexey Amunts , Karol Fiedorczuk , Thao T. Truong , Josephine Chandler , E. Peter Greenberg , V. Ramakrishnan

    The ribosome is the target of a large number of antibiotics. Here, we report a 3.4-Å-resolution crystal structure of bactobolin A bound to 70S ribosome–tRNA complex. The antibiotic binds at a previously unseen site in the 50S subunit and displaces tRNA bound at the P-site. It thus likely has a similar mechanism of action as blasticidin S despite binding to a different site. The structure also rationalizes previously identified resistance mutations.
    Graphical abstract




    Categories: Journal Articles
  • A Novel Open-Barrel Structure of Octameric Translin Reveals a Potential RNA Entryway
    [Feb 2015]

    Publication date: 27 February 2015
    Source:Journal of Molecular Biology, Volume 427, Issue 4

    Author(s): Elad Eliahoo , Ailie Marx , Haim Manor , Akram Alian

    The single-stranded DNA (ssDNA)/RNA binding protein translin was suggested to be involved in chromosomal translocations, telomere metabolism, and mRNA transport and translation. Oligonucleotide binding surfaces map within a closed cavity of translin octameric barrels, raising the question as to how DNA/RNA gain access to this inner cavity, particularly given that, to date, none of the barrel structures reported hint to an entryway. Here, we argue against a mechanism by which translin octamers may “dissociate and reassemble” upon RNA binding and report a novel “open”-barrel structure of human translin revealing a feasible DNA/RNA entryway into the cavity. Additionally, we report that translin not only is confined to binding of ssDNA oligonucleotides, or single-stranded extensions of double-stranded DNA (dsDNA), but also can bind single-stranded sequences internally embedded in dsDNA molecules.
    Graphical abstract




    Categories: Journal Articles
  • Intrinsically Disordered C-Terminal Tails of E. coli Single-Stranded DNA Binding Protein Regulate Cooperative Binding to Single-Stranded DNA
    [Feb 2015]

    Publication date: 27 February 2015
    Source:Journal of Molecular Biology, Volume 427, Issue 4

    Author(s): Alexander G. Kozlov , Elizabeth Weiland , Anuradha Mittal , Vince Waldman , Edwin Antony , Nicole Fazio , Rohit V. Pappu , Timothy M. Lohman

    The homotetrameric Escherichia coli single-stranded DNA binding protein (SSB) plays a central role in DNA replication, repair and recombination. E. coli SSB can bind to long single-stranded DNA (ssDNA) in multiple binding modes using all four subunits [(SSB)65 mode] or only two subunits [(SSB)35 binding mode], with the binding mode preference regulated by salt concentration and SSB binding density. These binding modes display very different ssDNA binding properties with the (SSB)35 mode displaying highly cooperative binding to ssDNA. SSB tetramers also bind an array of partner proteins, recruiting them to their sites of action. This is achieved through interactions with the last 9 amino acids (acidic tip) of the intrinsically disordered linkers (IDLs) within the four C-terminal tails connected to the ssDNA binding domains. Here, we show that the amino acid composition and length of the IDL affects the ssDNA binding mode preferences of SSB protein. Surprisingly, the number of IDLs and the lengths of individual IDLs together with the acidic tip contribute to highly cooperative binding in the (SSB)35 binding mode. Hydrodynamic studies and atomistic simulations suggest that the E. coli SSB IDLs show a preference for forming an ensemble of globular conformations, whereas the IDL from Plasmodium falciparum SSB forms an ensemble of more extended random coils. The more globular conformations correlate with cooperative binding.
    Graphical abstract




    Categories: Journal Articles
  • Heparan Sulfate Saccharides Modify Focal Adhesions: Implication in Mucopolysaccharidosis Neuropathophysiology
    [Feb 2015]

    Publication date: 27 February 2015
    Source:Journal of Molecular Biology, Volume 427, Issue 4

    Author(s): Julie Bruyère , Elise Roy , Jérôme Ausseil , Thomas Lemonnier , Guillaume Teyre , Delphine Bohl , Sandrine Etienne-Manneville , Hugues Lortat-Jacob , Jean Michel Heard , Sandrine Vitry

    Mucopolysaccharidoses type III (MPSIII, Sanfilippo syndrome) are genetic diseases due to deficient heparan sulfate (HS) saccharide digestion by lysosomal exoglycanases. Progressive accumulation of undigested saccharides causes early-onset behavioural and cognitive symptoms. The precise role of these saccharides in the pathophysiological cascade is still unclear. We showed that exposure of wild-type neural cells to exogenous soluble HS fragments of at least eight saccharides activated integrin-based focal adhesions (FAs), which attach cells to the extracellular matrix. FAs were constitutively activated in MPSIII type B astrocytes or neural stem cells unless undigested saccharides were cleared by exogenous supply of the missing exoglycanase. Defective cell polarisation and oriented migration in response to focal extracellular stimuli in affected cells suggest improper sensing of the environment. We consistently observed abnormal organisation of the rostral migratory stream in the brain of adult mice with MPSIII type B. These results suggest that cell polarisation and oriented migration defects participate to the neurological disorders associated with Sanfilippo syndrome.
    Graphical abstract




    Categories: Journal Articles
  • Differential Role of Base Pairs on gal Promoters Strength
    [Feb 2015]

    Publication date: 27 February 2015
    Source:Journal of Molecular Biology, Volume 427, Issue 4

    Author(s): Dale E.A. Lewis , Phuoc Le , Sankar Adhya

    Sequence alignments of promoters in prokaryotes postulated that the frequency of occurrence of a base pair at a given position of promoter elements reflects its contribution to intrinsic promoter strength. We directly assessed the contribution of the four base pairs in each position in the intrinsic promoter strength by keeping the context constant in Escherichia coli cAMP-CRP (cAMP receptor protein) regulated gal promoters by in vitro transcription assays. First, we show that base pair frequency within known consensus elements correlates well with promoter strength. Second, we observe some substitutions upstream of the ex-10 TG motif that are important for promoter function. Although the galP1 and P2 promoters overlap, only three positions where substitutions inactivated both promoters were found. We propose that RNA polymerase binds to the −12T base pair as part of double-stranded DNA while opening base pairs from −11A to +3 to form the single-stranded transcription bubble DNA during isomerization. The cAMP-CRP complex rescued some deleterious substitutions in the promoter region. The base pair roles and their flexibilities reported here for E. coli gal promoters may help construction of synthetic promoters in gene circuitry experiments in which overlapping promoters with differential controls may be warranted.
    Graphical abstract




    Categories: Journal Articles
  • Structure and Interactions of the CS Domain of Human H/ACA RNP Assembly Protein Shq1
    [Feb 2015]

    Publication date: 27 February 2015
    Source:Journal of Molecular Biology, Volume 427, Issue 4

    Author(s): Mahavir Singh , Zhonghua Wang , Duilio Cascio , Juli Feigon

    Shq1 is an essential protein involved in the early steps of biogenesis and assembly of H/ACA ribonucleoprotein particles (RNPs). Shq1 binds to dyskerin (Cbf5 in yeast) at an early step of H/ACA RNP assembly and is subsequently displaced by the H/ACA RNA. Shq1 contains an N-terminal CS and a C-terminal Shq1-specific domain (SSD). Dyskerin harbors many mutations associated with dyskeratosis congenita. Structures of yeast Shq1 SSD bound to Cbf5 revealed that only a subset of these mutations is in the SSD binding site, implicating another subset in the putative CS binding site. Here, we present the crystal structure of human Shq1 CS (hCS) and the nuclear magnetic resonance (NMR) and crystal structures of hCS containing a serine substitution for proline 22 that is associated with some prostate cancers. The structure of hCS is similar to yeast Shq1 CS domain (yCS) and consists of two β-sheets that form an immunoglobulin-like β-sandwich fold. The N-terminal affinity tag sequence AHHHHHH associates with a neighboring protein in the crystal lattice to form an extra β-strand. Deletion of this tag was required to get spectra suitable for NMR structure determination, while the tag was required for crystallization. NMR chemical shift perturbation (CSP) experiments with peptides derived from putative CS binding sites on dyskerin and Cbf5 revealed a conserved surface on CS important for Cbf5/dyskerin binding. A HADDOCK (high-ambiguity-driven protein–protein docking) model of a Shq1-Cbf5 complex that defines the position of CS domain in the pre-H/ACA RNP was calculated using the CSP data.
    Graphical abstract




    Categories: Journal Articles
  • Syndicate content