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Nature Structural & Molecular Biology

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https://www.readbyqxmd.com/read/28805810/trf2-binds-branched-dna-to-safeguard-telomere-integrity
#1
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...
August 14, 2017: Nature Structural & Molecular Biology
https://www.readbyqxmd.com/read/28805809/x-ray-structures-of-endothelin-etb-receptor-bound-to-clinical-antagonist-bosentan-and-its-analog
#2
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...
August 14, 2017: Nature Structural & Molecular Biology
https://www.readbyqxmd.com/read/28805808/constraints-and-consequences-of-the-emergence-of-amino-acid-repeats-in-eukaryotic-proteins
#3
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...
August 14, 2017: Nature Structural & Molecular Biology
https://www.readbyqxmd.com/read/28783151/hydroxylation-of-a-conserved-trna-modification-establishes-non-universal-genetic-code-in-echinoderm-mitochondria
#4
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)...
August 7, 2017: Nature Structural & Molecular Biology
https://www.readbyqxmd.com/read/28783150/katanin-spiral-and-ring-structures-shed-light-on-power-stroke-for-microtubule-severing
#5
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...
August 7, 2017: Nature Structural & Molecular Biology
https://www.readbyqxmd.com/read/28759050/rps26-directs-mrna-specific-translation-by-recognition-of-kozak-sequence-elements
#6
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...
July 31, 2017: Nature Structural & Molecular Biology
https://www.readbyqxmd.com/read/28759049/structural-basis-of-tir-domain-assembly-formation-in-mal-and-myd88-dependent-tlr4-signaling
#7
Thomas Ve, Parimala R Vajjhala, Andrew Hedger, Tristan Croll, Frank DiMaio, Shane Horsefield, Xiong Yu, Peter Lavrencic, Zahid Hassan, Garry P Morgan, Ashley Mansell, Mehdi Mobli, Ailis O'Carroll, Brieuc Chauvin, Yann Gambin, Emma Sierecki, Michael J Landsberg, Katryn J Stacey, Edward H Egelman, Bostjan Kobe
Toll-like receptor (TLR) signaling is a key innate immunity response to pathogens. Recruitment of signaling adapters such as MAL (TIRAP) and MyD88 to the TLRs requires Toll/interleukin-1 receptor (TIR)-domain interactions, which remain structurally elusive. Here we show that MAL TIR domains spontaneously and reversibly form filaments in vitro. They also form cofilaments with TLR4 TIR domains and induce formation of MyD88 assemblies. A 7-Å-resolution cryo-EM structure reveals a stable MAL protofilament consisting of two parallel strands of TIR-domain subunits in a BB-loop-mediated head-to-tail arrangement...
July 31, 2017: Nature Structural & Molecular Biology
https://www.readbyqxmd.com/read/28759048/decoding-the-selectivity-of-eif2%C3%AE-holophosphatases-and-ppp1r15a-inhibitors
#8
Marta Carrara, Anna Sigurdardottir, Anne Bertolotti
The reversible phosphorylation of proteins controls most cellular functions. Protein kinases have been popular drug targets, unlike phosphatases, which remain a drug discovery challenge. Guanabenz and Sephin1 are selective inhibitors of the phosphatase regulatory subunit PPP1R15A (R15A) that prolong the benefit of eIF2α phosphorylation, thereby protecting cells from proteostatic defects. In mice, Sephin1 prevents two neurodegenerative diseases, Charcot-Marie-Tooth 1B (CMT-1B) and SOD1-mediated amyotrophic lateral sclerosis (ALS)...
July 31, 2017: Nature Structural & Molecular Biology
https://www.readbyqxmd.com/read/28741612/an-information-theoretic-framework-reveals-a-tunable-allosteric-network-in-group-ii-chaperonins
#9
Tom Lopez, Kevin Dalton, Anthony Tomlinson, Vijay Pande, Judith Frydman
ATP-dependent allosteric regulation of the ring-shaped group II chaperonins remains ill defined, in part because their complex oligomeric topology has limited the success of structural techniques in suggesting allosteric determinants. Further, their high sequence conservation has hindered the prediction of allosteric networks using mathematical covariation approaches. Here, we develop an information theoretic strategy that is robust to residue conservation and apply it to group II chaperonins. We identify a contiguous network of covarying residues that connects all nucleotide-binding pockets within each chaperonin ring...
July 24, 2017: Nature Structural & Molecular Biology
https://www.readbyqxmd.com/read/28741611/an-antimicrobial-peptide-that-inhibits-translation-by-trapping-release-factors-on-the-ribosome
#10
Tanja Florin, Cristina Maracci, Michael Graf, Prajwal Karki, Dorota Klepacki, Otto Berninghausen, Roland Beckmann, Nora Vázquez-Laslop, Daniel N Wilson, Marina V Rodnina, Alexander S Mankin
Many antibiotics stop bacterial growth by inhibiting different steps of protein synthesis. However, no specific inhibitors of translation termination are known. Proline-rich antimicrobial peptides, a component of the antibacterial defense system of multicellular organisms, interfere with bacterial growth by inhibiting translation. Here we show that Api137, a derivative of the insect-produced antimicrobial peptide apidaecin, arrests terminating ribosomes using a unique mechanism of action. Api137 binds to the Escherichia coli ribosome and traps release factor (RF) RF1 or RF2 subsequent to the release of the nascent polypeptide chain...
July 24, 2017: Nature Structural & Molecular Biology
https://www.readbyqxmd.com/read/28771464/two-chaperones-locked-in-an-embrace-structure-and-function-of-the-ribosome-associated-complex-rac
#11
REVIEW
Ying Zhang, Irmgard Sinning, Sabine Rospert
Chaperones, which assist protein folding are essential components of every living cell. The yeast ribosome-associated complex (RAC) is a chaperone that is highly conserved in eukaryotic cells. The RAC consists of the J protein Zuo1 and the unconventional Hsp70 homolog Ssz1. The RAC heterodimer stimulates the ATPase activity of the ribosome-bound Hsp70 homolog Ssb, which interacts with nascent polypeptide chains to facilitate de novo protein folding. In addition, the RAC-Ssb system is required to maintain the fidelity of protein translation...
August 3, 2017: Nature Structural & Molecular Biology
https://www.readbyqxmd.com/read/28771463/dueling-rna-binding-proteins-promote-translational-activation
#12
Paul Lasko
No abstract text is available yet for this article.
August 3, 2017: Nature Structural & Molecular Biology
https://www.readbyqxmd.com/read/28771462/a-tetrad-of-chromatin-interactions-for-chromosome-pairing-in-x-inactivation
#13
Ivan Krivega, Ann Dean
No abstract text is available yet for this article.
August 3, 2017: Nature Structural & Molecular Biology
https://www.readbyqxmd.com/read/28714993/a-two-helix-motif-positions-the-lysophosphatidic-acid-acyltransferase-active-site-for-catalysis-within-the-membrane-bilayer
#14
Rosanna M Robertson, Jiangwei Yao, Stefan Gajewski, Gyanendra Kumar, Erik W Martin, Charles O Rock, Stephen W White
Phosphatidic acid (PA), the central intermediate in membrane phospholipid synthesis, is generated by two acyltransferases in a pathway conserved in all life forms. The second step in this pathway is catalyzed by 1-acyl-sn-glycerol-3-phosphate acyltransferase, called PlsC in bacteria. Here we present the crystal structure of PlsC from Thermotoga maritima, revealing an unusual hydrophobic/aromatic N-terminal two-helix motif linked to an acyltransferase αβ-domain that contains the catalytic HX4D motif. PlsC dictates the acyl chain composition of the 2-position of phospholipids, and the acyl chain selectivity 'ruler' is an appropriately placed and closed hydrophobic tunnel...
August 2017: Nature Structural & Molecular Biology
https://www.readbyqxmd.com/read/28714992/musashi-1-regulates-the-timing-and-extent-of-meiotic-mrna-translational-activation-by-promoting-the-use-of-specific-cpes
#15
Laure Weill, Eulàlia Belloc, Chiara Lara Castellazzi, Raúl Méndez
The translational reactivation of maternal mRNAs encoding meiotic drivers in vertebrates is accomplished mainly by cytoplasmic polyadenylation. The cytoplasmic polyadenylation elements (CPEs) present in the 3' untranslated regions (3' UTRs) of these transcripts, together with their cognate CPE-binding proteins (CPEBs), define a combinatorial code that determines the timing and extent of translational activation upon meiosis resumption. In addition, the RNA-binding protein Musashi1 (Msi1) regulates polyadenylation of CPE-containing mRNAs by a yet undefined CPEB-dependent or CPEB-independent mechanism...
August 2017: Nature Structural & Molecular Biology
https://www.readbyqxmd.com/read/28692038/par-terra-directs-homologous-sex-chromosome-pairing
#16
Hsueh-Ping Chu, John E Froberg, Barry Kesner, Hyun Jung Oh, Fei Ji, Ruslan Sadreyev, Stefan F Pinter, Jeannie T Lee
In mammals, homologous chromosomes rarely pair outside meiosis. One exception is the X chromosome, which transiently pairs during X-chromosome inactivation (XCI). How two chromosomes find each other in 3D space is not known. Here, we reveal a required interaction between the X-inactivation center (Xic) and the telomere in mouse embryonic stem (ES) cells. The subtelomeric, pseudoautosomal regions (PARs) of the two sex chromosomes (X and Y) also undergo pairing in both female and male cells. PARs transcribe a class of telomeric RNA, dubbed PAR-TERRA, which accounts for a vast majority of all TERRA transcripts...
August 2017: Nature Structural & Molecular Biology
https://www.readbyqxmd.com/read/28671667/mechanochemical-evolution-of-the-giant-muscle-protein-titin-as-inferred-from-resurrected-proteins
#17
Aitor Manteca, Jörg Schönfelder, Alvaro Alonso-Caballero, Marie J Fertin, Nerea Barruetabeña, Bruna F Faria, Elias Herrero-Galán, Jorge Alegre-Cebollada, David De Sancho, Raul Perez-Jimenez
The sarcomere-based structure of muscles is conserved among vertebrates; however, vertebrate muscle physiology is extremely diverse. A molecular explanation for this diversity and its evolution has not been proposed. We use phylogenetic analyses and single-molecule force spectroscopy (smFS) to investigate the mechanochemical evolution of titin, a giant protein responsible for the elasticity of muscle filaments. We resurrect eight-domain fragments of titin corresponding to the common ancestors to mammals, sauropsids, and tetrapods, which lived 105-356 Myr ago, and compare them with titin fragments from some of their modern descendants...
August 2017: Nature Structural & Molecular Biology
https://www.readbyqxmd.com/read/28671666/multi-domain-utilization-by-tut4-and-tut7-in-control-of-let-7-biogenesis
#18
Christopher R Faehnle, Jack Walleshauser, Leemor Joshua-Tor
The uridyl transferases TUT4 and TUT7 (collectively called TUT4(7)) switch between two modes of activity, either promoting expression of let-7 microRNA (monoU) or marking it for degradation (oligoU). Lin28 modulates the switch via recruitment of TUT4(7) to the precursor pre-let-7 in stem cells and human cancers. We found that TUT4(7) utilize two multidomain functional modules during the switch from monoU to oligoU. The catalytic module (CM) is essential for both activities, while the Lin28-interacting module (LIM) is indispensable for oligoU...
August 2017: Nature Structural & Molecular Biology
https://www.readbyqxmd.com/read/28671665/asparagine-endopeptidase-cleaves-%C3%AE-synuclein-and-mediates-pathologic-activities-in-parkinson-s-disease
#19
Zhentao Zhang, Seong Su Kang, Xia Liu, Eun Hee Ahn, Zhaohui Zhang, Li He, P Michael Iuvone, Duc M Duong, Nicholas T Seyfried, Matthew J Benskey, Fredric P Manfredsson, Lingjing Jin, Yi E Sun, Jian-Zhi Wang, Keqiang Ye
Aggregated forms of α-synuclein play a crucial role in the pathogenesis of synucleinopathies such as Parkinson's disease (PD). However, the molecular mechanisms underlying the pathogenic effects of α-synuclein are not completely understood. Here we show that asparagine endopeptidase (AEP) cleaves human α-synuclein, triggers its aggregation and escalates its neurotoxicity, thus leading to dopaminergic neuronal loss and motor impairments in a mouse model. AEP is activated and cleaves human α-synuclein at N103 in an age-dependent manner...
August 2017: Nature Structural & Molecular Biology
https://www.readbyqxmd.com/read/28671664/regulator-dependent-mechanisms-of-c3b-processing-by-factor-i-allow-differentiation-of-immune-responses
#20
Xiaoguang Xue, Jin Wu, Daniel Ricklin, Federico Forneris, Patrizia Di Crescenzio, Christoph Q Schmidt, Joke Granneman, Thomas H Sharp, John D Lambris, Piet Gros
The complement system labels microbes and host debris for clearance. Degradation of surface-bound C3b is pivotal to direct immune responses and protect host cells. How the serine protease factor I (FI), assisted by regulators, cleaves either two or three distant peptide bonds in the CUB domain of C3b remains unclear. We present a crystal structure of C3b in complex with FI and regulator factor H (FH; domains 1-4 with 19-20). FI binds C3b-FH between FH domains 2 and 3 and a reoriented C3b C-terminal domain and docks onto the first scissile bond, while stabilizing its catalytic domain for proteolytic activity...
August 2017: Nature Structural & Molecular Biology
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