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Nature Structural & Molecular Biology

Alan Brown, Sorbhi Rathore, Dari Kimanius, Shintaro Aibara, Xiao-Chen Bai, Joanna Rorbach, Alexey Amunts, V Ramakrishnan
Mammalian mitochondrial ribosomes (mitoribosomes) have less rRNA content and 36 additional proteins compared with the evolutionarily related bacterial ribosome. These differences make the assembly of mitoribosomes more complex than the assembly of bacterial ribosomes, but the molecular details of mitoribosomal biogenesis remain elusive. Here, we report the structures of two late-stage assembly intermediates of the human mitoribosomal large subunit (mt-LSU) isolated from a native pool within a human cell line and solved by cryo-EM to ∼3-Å resolution...
September 11, 2017: Nature Structural & Molecular Biology
Gavin J Knott, Alexandra East-Seletsky, Joshua C Cofsky, James M Holton, Emeric Charles, Mitchell R O'Connell, Jennifer A Doudna
CRISPR adaptive immune systems protect bacteria from infections by deploying CRISPR RNA (crRNA)-guided enzymes to recognize and cut foreign nucleic acids. Type VI-A CRISPR-Cas systems include the Cas13a enzyme, an RNA-activated RNase capable of crRNA processing and single-stranded RNA degradation upon target-transcript binding. Here we present the 2.0-Å resolution crystal structure of a crRNA-bound Lachnospiraceae bacterium Cas13a (LbaCas13a), representing a recently discovered Cas13a enzyme subtype. This structure and accompanying biochemical experiments define the Cas13a catalytic residues that are directly responsible for crRNA maturation...
September 11, 2017: Nature Structural & Molecular Biology
Carrie Bernecky, Jürgen M Plitzko, Patrick Cramer
During transcription, RNA polymerase II (Pol II) associates with the conserved elongation factor DSIF. DSIF renders the elongation complex stable and functions during Pol II pausing and RNA processing. We combined cryo-EM and X-ray crystallography to determine the structure of the mammalian Pol II-DSIF elongation complex at a nominal resolution of 3.4 Å. Human DSIF has a modular structure with two domains forming a DNA clamp, two domains forming an RNA clamp, and one domain buttressing the RNA clamp. The clamps maintain the transcription bubble, position upstream DNA, and retain the RNA transcript in the exit tunnel...
September 11, 2017: Nature Structural & Molecular Biology
Raghu R Edupuganti, Simon Geiger, Rik G H Lindeboom, Hailing Shi, Phillip J Hsu, Zhike Lu, Shuang-Yin Wang, Marijke P A Baltissen, Pascal W T C Jansen, Martin Rossa, Markus Müller, Hendrik G Stunnenberg, Chuan He, Thomas Carell, Michiel Vermeulen
RNA modifications are integral to the regulation of RNA metabolism. One abundant mRNA modification is N(6)-methyladenosine (m(6)A), which affects various aspects of RNA metabolism, including splicing, translation and degradation. Current knowledge about the proteins recruited to m(6)A to carry out these molecular processes is still limited. Here we describe comprehensive and systematic mass-spectrometry-based screening of m(6)A interactors in various cell types and sequence contexts. Among the main findings, we identified G3BP1 as a protein that is repelled by m(6)A and positively regulates mRNA stability in an m(6)A-regulated manner...
September 4, 2017: Nature Structural & Molecular Biology
Feng Hong, Bei Liu, Bill X Wu, Jordan Morreall, Brady Roth, Christopher Davies, Shaoli Sun, J Alan Diehl, Zihai Li
The unfolded protein response (UPR) in the endoplasmic reticulum (ER) is a highly conserved protein-quality-control mechanism critical for cells to make survival-or-death decisions under ER-stress conditions. However, how UPR sensors are activated remains unclear. Here, we report that ER luminal protein canopy homolog 2 (CNPY2) is released from grp78 upon ER stress. Free CNPY2 then engages protein kinase R-like ER kinase (PERK) to induce expression of the transcription factor C/EBP homologous protein (CHOP), thereby initiating the UPR...
September 4, 2017: Nature Structural & Molecular Biology
Victor Pau, Yufeng Zhou, Yajamana Ramu, Yanping Xu, Zhe Lu
C-type inactivation underlies important roles played by voltage-gated K(+) (Kv) channels. Functional studies have provided strong evidence that a common underlying cause of this type of inactivation is an alteration near the extracellular end of the channel's ion-selectivity filter. Unlike N-type inactivation, which is known to reflect occlusion of the channel's intracellular end, the structural mechanism of C-type inactivation remains controversial and may have many detailed variations. Here we report that in voltage-gated Shaker K(+) channels lacking N-type inactivation, a mutation enhancing inactivation disrupts the outermost K(+) site in the selectivity filter...
August 28, 2017: Nature Structural & Molecular Biology
Li Jiang, Changwei Shao, Qi-Jia Wu, Geng Chen, Jie Zhou, Bo Yang, Hairi Li, Lan-Tao Gou, Yi Zhang, Yangming Wang, Gene W Yeo, Yu Zhou, Xiang-Dong Fu
MicroRNA (miRNA) biogenesis is known to be modulated by a variety of RNA-binding proteins (RBPs), but in most cases, individual RBPs appear to influence the processing of a small subset of target miRNAs. Here, we report that the RNA-binding NONO-PSF heterodimer binds a large number of expressed pri-miRNAs in HeLa cells to globally enhance pri-miRNA processing by the Drosha-DGCR8 Microprocessor. NONO and PSF are key components of paraspeckles organized by the long noncoding RNA (lncRNA) NEAT1. We further demonstrate that NEAT1 also has a profound effect on global pri-miRNA processing...
August 28, 2017: Nature Structural & Molecular Biology
Yingnan Zhang, Mark Ultsch, Nicholas J Skelton, Daniel J Burdick, Maureen H Beresini, Wei Li, Monica Kong-Beltran, Andrew Peterson, John Quinn, Cecilia Chiu, Yan Wu, Steven Shia, Paul Moran, Paola Di Lello, Charles Eigenbrot, Daniel Kirchhofer
Proprotein convertase subtilisin/kexin type 9 (PCSK9) regulates plasma LDL cholesterol (LDL-c) levels by promoting the degradation of liver LDL receptors (LDLRs). Antibodies that inhibit PCSK9 binding to the EGF(A) domain of the LDLR are effective in lowering LDL-c. However, the discovery of small-molecule therapeutics is hampered by difficulty in targeting the relatively flat EGF(A)-binding site on PCSK9. Here we demonstrate that it is possible to target this site, based on the finding that the PCSK9 P' helix displays conformational flexibility...
August 21, 2017: Nature Structural & Molecular Biology
Antonina Hafner, Jacob Stewart-Ornstein, Jeremy E Purvis, William C Forrester, Martha L Bulyk, Galit Lahav
The dynamics of transcription factors play important roles in a variety of biological systems. However, the mechanisms by which these dynamics are decoded into different transcriptional responses are not well understood. Here we focus on the dynamics of the tumor-suppressor protein p53, which exhibits a series of pulses in response to DNA damage. We performed time course RNA sequencing (RNA-seq) and chromatin immunoprecipitation sequencing (ChIP-seq) measurements to determine how p53 oscillations are linked with gene expression genome wide...
August 21, 2017: Nature Structural & Molecular Biology
Inês Chen
No abstract text is available yet for this article.
September 7, 2017: Nature Structural & Molecular Biology
Mingliang Jin, Yao Cong
No abstract text is available yet for this article.
September 7, 2017: Nature Structural & Molecular Biology
Cohue Peña, Ed Hurt, Vikram Govind Panse
Eukaryotic ribosome synthesis is a complex, energy-consuming process that takes place across the nucleolus, nucleoplasm and cytoplasm and requires more than 200 conserved assembly factors. Here, we discuss mechanisms by which the ribosome assembly and nucleocytoplasmic transport machineries collaborate to produce functional ribosomes. We also highlight recent cryo-EM studies that provided unprecedented snapshots of ribosomes during assembly and quality control.
September 7, 2017: Nature Structural & Molecular Biology
Rika Ohkubo, Danica Chen
No abstract text is available yet for this article.
September 7, 2017: Nature Structural & Molecular Biology
Rakesh Pathak, Robert Feil
No abstract text is available yet for this article.
September 7, 2017: Nature Structural & Molecular Biology
Isabelle Schmutz, Leonid Timashev, Wei Xie, Dinshaw J Patel, Titia de Lange
Although t-loops protect telomeres, they are at risk of cleavage by Holliday junction (HJ) resolvases if branch migration converts the three-way t-loop junction into four-way HJs. T-loop cleavage is repressed by the TRF2 basic domain, which binds three- and four-way junctions and protects HJs in vitro. By replacing the basic domain with bacterial-protein domains binding three- and four-way junctions, we demonstrated the in vivo relevance of branched-DNA binding. Branched-DNA binding also repressed PARP1, presumably by masking the PARP1 site in the t-loop junction...
September 2017: Nature Structural & Molecular Biology
Wataru Shihoya, Tomohiro Nishizawa, Keitaro Yamashita, Asuka Inoue, Kunio Hirata, Francois Marie Ngako Kadji, Akiko Okuta, Kazutoshi Tani, Junken Aoki, Yoshinori Fujiyoshi, Tomoko Doi, Osamu Nureki
Endothelin receptors (ETRs) have crucial roles in vascular control and are targets for drugs designed to treat circulatory-system diseases and cancer progression. The nonpeptide dual-ETR antagonist bosentan is the first oral drug approved to treat pulmonary arterial hypertension. Here we report crystal structures of human endothelin ETB receptor bound to bosentan and to the ETB-selective analog K-8794, at 3.6-Å and 2.2-Å resolution, respectively. The K-8794-bound structure reveals the detailed water-mediated hydrogen-bonding network at the transmembrane core, which could account for the weak negative allosteric modulation of ETB by Na(+) ions...
September 2017: Nature Structural & Molecular Biology
Sreenivas Chavali, Pavithra L Chavali, Guilhem Chalancon, Natalia Sanchez de Groot, Rita Gemayel, Natasha S Latysheva, Elizabeth Ing-Simmons, Kevin J Verstrepen, Santhanam Balaji, M Madan Babu
Proteins with amino acid homorepeats have the potential to be detrimental to cells and are often associated with human diseases. Why, then, are homorepeats prevalent in eukaryotic proteomes? In yeast, homorepeats are enriched in proteins that are essential and pleiotropic and that buffer environmental insults. The presence of homorepeats increases the functional versatility of proteins by mediating protein interactions and facilitating spatial organization in a repeat-dependent manner. During evolution, homorepeats are preferentially retained in proteins with stringent proteostasis, which might minimize repeat-associated detrimental effects such as unregulated phase separation and protein aggregation...
September 2017: Nature Structural & Molecular Biology
Asuteka Nagao, Mitsuhiro Ohara, Kenjyo Miyauchi, Shin-Ichi Yokobori, Akihiko Yamagishi, Kimitsuna Watanabe, Tsutomu Suzuki
The genetic code is not frozen but still evolving, which can result in the acquisition of 'dialectal' codons that deviate from the universal genetic code. RNA modifications in the anticodon region of tRNAs play a critical role in establishing such non-universal genetic codes. In echinoderm mitochondria, the AAA codon specifies asparagine instead of lysine. By analyzing mitochondrial (mt-) tRNA(Lys) isolated from the sea urchin (Mesocentrotus nudus), we discovered a novel modified nucleoside, hydroxy-N(6)-threonylcarbamoyladenosine (ht(6)A), 3' adjacent to the anticodon (position 37)...
September 2017: Nature Structural & Molecular Biology
Elena Zehr, Agnieszka Szyk, Grzegorz Piszczek, Ewa Szczesna, Xiaobing Zuo, Antonina Roll-Mecak
Microtubule-severing enzymes katanin, spastin and fidgetin are AAA ATPases important for the biogenesis and maintenance of complex microtubule arrays in axons, spindles and cilia. Because of a lack of known 3D structures for these enzymes, their mechanism of action has remained poorly understood. Here we report the X-ray crystal structure of the monomeric AAA katanin module from Caenorhabditis elegans and cryo-EM reconstructions of the hexamer in two conformations. The structures reveal an unexpected asymmetric arrangement of the AAA domains mediated by structural elements unique to microtubule-severing enzymes and critical for their function...
September 2017: Nature Structural & Molecular Biology
Max B Ferretti, Homa Ghalei, Ethan A Ward, Elizabeth L Potts, Katrin Karbstein
We describe a novel approach to separate two ribosome populations from the same cells and use this method in combination with RNA-seq to identify mRNAs bound to Saccharomyces cerevisiae ribosomes with and without Rps26, a protein linked to the pathogenesis of Diamond-Blackfan anemia (DBA). These analyses reveal that Rps26 contributes to mRNA-specific translation by recognition of the Kozak sequence in well-translated mRNAs and that Rps26-deficient ribosomes preferentially translate mRNA from select stress-response pathways...
September 2017: Nature Structural & Molecular Biology
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