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Querol-Audi J.,University of California at Berkeley | Querol-Audi J.,Molecular Biology Institute of Barcelona IBMB CSIC | Sun C.,University of California at Berkeley | Vogan J.M.,University of California at Berkeley | And 6 more authors.
Structure | Year: 2013

Eukaryotic translation initiation factor 3 (eIF3) plays a central role in protein synthesis by organizing the formation of the 43S preinitiation complex. Using genetic tag visualization by electron microscopy, we reveal the molecular organization of ten human eIF3 subunits, including an octameric core. The structure of eIF3 bears a close resemblance to that of the proteasome lid, with a conserved spatial organization of eight core subunits containing PCI and MPN domains that coordinate functional interactions in both complexes. We further show that eIF3 subunits a and c interact with initiation factors eIF1 and eIF1A, which control the stringency of start codon selection. Finally, we find that subunit j, which modulates messenger RNA interactions with the small ribosomal subunit, makes multiple independent interactions with the eIF3 octameric core. These results highlight the conserved architecture of eIF3 and how it scaffolds key factors that control translation initiation in higher eukaryotes, including humans. © 2013 Elsevier Ltd. All rights reserved.

Mebs S.,Free University of Berlin | Chilleck M.A.,Humboldt University of Berlin | Meindl K.,Molecular Biology Institute of Barcelona IBMB CSIC | Hubschle C.B.,University of Bayreuth
Journal of Physical Chemistry A | Year: 2014

Despite numerous advanced and widely distributed bonding theories such as MO, VB, NBO, AIM, and ELF/ELI-D, complex modes of bonding such as M-Cp (R) interactions (hapticities) in asymmetrical metallocenes or weak intramolecular interactions (e.g., hydrogen-hydrogen (H⋯H) bonds) still remain a challenge for these theories in terms of defining whether or not an atom-atom interaction line (a "chemical bond") should be drawn. In this work the intramolecular Zn-CCp(R) (R = Me, -(CH 2)2NMe2, and -(CH2) 3NMe2) and H⋯H connectivity of a systematic set of 12 zincocene-related compounds is analyzed in terms of AIM and ELI-D topology combined with the recently introduced aspherical stockholder fragment (ASF) surfaces. This computational analysis unravels a distinct dependency of the AIM and ELI-D topology against the molecular geometry for both types of interactions, which confirms and extends earlier findings on smaller sets of compounds. According to these results the complete real-space topology including strong, medium, and weak interactions of very large compounds such as proteins may be reliably predicted by sole inspection of accurately determined molecular geometries, which would on the one hand afford new applications (e.g., accurate estimation of numbers, types, and strengths of intra- and intermolecular interactions) and on the other hand have deep implications on the significance of the method. © 2014 American Chemical Society.

Repiso A.,University of Barcelona | Repiso A.,Molecular Biology Institute of Barcelona IBMB CSIC | Bergantinos C.,University of Barcelona | Bergantinos C.,Columbia University | Serras F.,University of Barcelona
Development (Cambridge) | Year: 2013

To understand the cellular parameters that govern Drosophila wing disc regeneration, we genetically eliminated specific stripes of the wing disc along the proximodistal axis and used vein and intervein markers to trace tissue regeneration. We found that veins could regenerate interveins and vice versa, indicating respecification of cell fates. Moreover, respecification occurred in cells close to the wound. The newly generated domains were intercalated to fill in the missing parts. This intercalation was driven by increased proliferation, accompanied by changes in the orientation of the cell divisions. This reorientation depended on Fat (Ft) and Crumbs (Crb), which acted, at least partly, to control the activity of the effector of the Hippo pathway, Yorkie (Yki). Increased Yki, which promotes proliferation, affected the final shape and size. Heterozygous ft or crb, which normally elicit size and shape defects in regenerated wings, could be rescued by yki heterozygosity. Thus, Ft and Crb act as sensors to drive cell orientation during intercalary regeneration and control Yki levels to ensure a proper balance between proliferation and cell reorientation. We propose a model based on intercalation of missing cell identities, in which a coordinated balance between orientation and proliferation is required for normal organ shape and size. © 2013. Published by The Company of Biologists Ltd.

Thienpont B.,CSIC - Institute of Environmental Assessment And Water Research | Tingaud-Sequeira A.,University of Bordeaux 1 | Prats E.,Molecular Biology Institute of Barcelona IBMB CSIC | Barata C.,CSIC - Institute of Environmental Assessment And Water Research | And 2 more authors.
Environmental Science and Technology | Year: 2011

Thyroxine-immunofluorescence quantitative disruption test (TIQDT) was designed to provide a simple, rapid, alternative bioassay for assessing the potential of chemical pollutants and drugs to disrupt thyroid gland function. This study demonstrated that zebrafish eleutheroembryos provided a suitable vertebrate model, not only for screening the potential thyroid disrupting effect of molecules, but also for estimating the potential hazards associated with exposure to chemicals directly impairing thyroxine (T4) synthesis. Amitrole, potassium perchlorate, potassium thiocyanate, methimazole (MMI), phloroglucinol, 6-propyl-2-thiouracil, ethylenethiourea, benzophenone-2, resorcinol, pyrazole, sulfamethoxazole, sodium bromide, mancozeb, and genistein were classified as thyroid gland function disruptors. Concordance between TIQDT on zebrafish and mammalian published data was very high and the physiological relevance of T4-intrafollicular content was clearly higher than regulation at the transcriptional level of tg or slc5a5. Moreover, concentration-response analysis provided information about the thyroid disrupting potency and hazard of selected positive compounds. Finally, the effect of perchlorate, but not MMI, was completely rescued by low-micromolar amounts of iodide. TIQDT performed on zebrafish eleutheroembryos is an alternative whole-organism screening assay that provides relevant information for environmental and human risk assessments. © 2011 American Chemical Society.

Smith M.D.,University of California at Berkeley | Gu Y.,University of California at Berkeley | Querol-Audi J.,University of California at Berkeley | Querol-Audi J.,Molecular Biology Institute of Barcelona IBMB CSIC | And 4 more authors.
PLoS ONE | Year: 2013

Eukaryotic translation initiation factor 3 (eIF3) is a key regulator of translation initiation, but its in vivo assembly and molecular functions remain unclear. Here we show that eIF3 from Neurospora crassa is structurally and compositionally similar to human eIF3. N. crassa eIF3 forms a stable 12-subunit complex linked genetically and biochemically to the 13th subunit, eIF3j, which in humans modulates mRNA start codon selection. Based on N. crassa genetic analysis, most subunits in eIF3 are essential. Subunits that can be deleted (e, h, k and l) map to the right side of the eIF3 complex, suggesting that they may coordinately regulate eIF3 function. Consistent with this model, subunits eIF3k and eIF3l are incorporated into the eIF3 complex as a pair, and their insertion depends on the presence of subunit eIF3h, a key regulator of vertebrate development. Comparisons to other eIF3 complexes suggest that eIF3 assembles around an eIF3a and eIF3c dimer, which may explain the coordinated regulation of human eIF3 levels. Taken together, these results show that Neurospora crassa eIF3 provides a tractable system for probing the structure and function of human-like eIF3 in the context of living cells. © 2013 Smith et al.

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