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Nature Structural & Molecular Biology

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https://www.readbyqxmd.com/read/29131142/a-consensus-model-of-human-apolipoprotein-a-i-in-its-monomeric-and-lipid-free-state
#1
John T Melchior, Ryan G Walker, Allison L Cooke, Jamie Morris, Mark Castleberry, Thomas B Thompson, Martin K Jones, Hyun D Song, Kerry-Anne Rye, Michael N Oda, Mary G Sorci-Thomas, Michael J Thomas, Jay W Heinecke, Xiaohu Mei, David Atkinson, Jere P Segrest, Sissel Lund-Katz, Michael C Phillips, W Sean Davidson
Apolipoprotein (apo)A-I is an organizing scaffold protein that is critical to high-density lipoprotein (HDL) structure and metabolism, probably mediating many of its cardioprotective properties. However, HDL biogenesis is poorly understood, as lipid-free apoA-I has been notoriously resistant to high-resolution structural study. Published models from low-resolution techniques share certain features but vary considerably in shape and secondary structure. To tackle this central issue in lipoprotein biology, we assembled a team of structural biologists specializing in apolipoproteins and set out to build a consensus model of monomeric lipid-free human apoA-I...
November 13, 2017: Nature Structural & Molecular Biology
https://www.readbyqxmd.com/read/29131141/programming-asynchronous-replication-in-stem-cells
#2
Hagit Masika, Marganit Farago, Merav Hecht, Reba Condiotti, Kirill Makedonski, Yosef Buganim, Tal Burstyn-Cohen, Yehudit Bergman, Howard Cedar
Many regions of the genome replicate asynchronously and are expressed monoallelically. It is thought that asynchronous replication may be involved in choosing one allele over the other, but little is known about how these patterns are established during development. We show that, unlike somatic cells, which replicate in a clonal manner, embryonic and adult stem cells are programmed to undergo switching, such that daughter cells with an early-replicating paternal allele are derived from mother cells that have a late-replicating paternal allele...
November 13, 2017: Nature Structural & Molecular Biology
https://www.readbyqxmd.com/read/29106414/cryo-em-structures-of-the-human-endolysosomal-trpml3-channel-in-three-distinct-states
#3
Xiaoyuan Zhou, Minghui Li, Deyuan Su, Qi Jia, Huan Li, Xueming Li, Jian Yang
TRPML3 channels are mainly localized to endolysosomes and play a critical role in the endocytic pathway. Their dysfunction causes deafness and pigmentation defects in mice. TRPML3 activity is inhibited by low endolysosomal pH. Here we present cryo-electron microscopy (cryo-EM) structures of human TRPML3 in the closed, agonist-activated, and low-pH-inhibited states, with resolutions of 4.06, 3.62, and 4.65 Å, respectively. The agonist ML-SA1 lodges between S5 and S6 and opens an S6 gate. A polycystin-mucolipin domain (PMD) forms a luminal cap...
November 6, 2017: Nature Structural & Molecular Biology
https://www.readbyqxmd.com/read/29106413/tfiih-generates-a-six-base-pair-open-complex-during-rnap-ii-transcription-initiation-and-start-site-scanning
#4
Eric J Tomko, James Fishburn, Steven Hahn, Eric A Galburt
Eukaryotic mRNA transcription initiation is directed by the formation of the megadalton-sized preinitiation complex (PIC). After PIC formation, double-stranded DNA (dsDNA) is unwound to form a single-stranded DNA bubble, and the template strand is loaded into the polymerase active site. DNA opening is catalyzed by Ssl2 (XPB), the dsDNA translocase subunit of the basal transcription factor TFIIH. In yeast, transcription initiation proceeds through a scanning phase during which downstream DNA is searched for optimal start sites...
November 6, 2017: Nature Structural & Molecular Biology
https://www.readbyqxmd.com/read/29106412/short-poly-a-tails-are-a-conserved-feature-of-highly-expressed-genes
#5
Sarah Azoubel Lima, Laura B Chipman, Angela L Nicholson, Ying-Hsin Chen, Brian A Yee, Gene W Yeo, Jeff Coller, Amy E Pasquinelli
Poly(A) tails are important elements in mRNA translation and stability, although recent genome-wide studies have concluded that poly(A) tail length is generally not associated with translational efficiency in nonembryonic cells. To investigate whether poly(A) tail size might be coupled to gene expression in an intact organism, we used an adapted TAIL-seq protocol to measure poly(A) tails in Caenorhabditis elegans. Surprisingly, we found that well-expressed transcripts contain relatively short, well-defined tails...
November 6, 2017: Nature Structural & Molecular Biology
https://www.readbyqxmd.com/read/29106411/extrachromosomal-telomere-repeat-dna-is-linked-to-alt-development-via-cgas-sting-dna-sensing-pathway
#6
Yi-An Chen, Yi-Ling Shen, Hsuan-Yu Hsia, Yee-Peng Tiang, Tzu-Ling Sung, Liuh-Yow Chen
Extrachromosomal telomere repeat (ECTR) DNA is unique to cancer cells that maintain telomeres through the alternative lengthening of telomeres (ALT) pathway, but the role of ECTRs in ALT development remains elusive. We found that induction of ECTRs in normal human fibroblasts activated the cGAS-STING-TBK1-IRF3 signaling axis to trigger IFNβ production and a type I interferon response, resulting in cell-proliferation defects. In contrast, ALT cancer cells are commonly defective in sensing cytosolic DNA. We found that STING expression was inhibited in ALT cancer cell lines and transformed ALT cells...
November 6, 2017: Nature Structural & Molecular Biology
https://www.readbyqxmd.com/read/29083416/telomeric-terb1-trf1-interaction-is-crucial-for-male-meiosis
#7
Juanjuan Long, Chenhui Huang, Yanyan Chen, Ying Zhang, Shaohua Shi, Ligang Wu, Yie Liu, Chengyu Liu, Jian Wu, Ming Lei
During meiotic prophase, the meiosis-specific telomere-binding protein TERB1 regulates chromosome movement required for homologous pairing and recombination by interacting with the telomeric shelterin subunit TRF1. Here, we report the crystal structure of the TRF1-binding motif of human TERB1 in complex with the TRFH domain of TRF1. Notably, specific disruption of the TERB1-TRF1 interaction by a point mutation in the mouse Terb1 gene results in infertility only in males. We find that this mutation causes an arrest in the zygotene-early pachytene stage and mild telomere abnormalities of autosomes but unpaired X and Y chromosomes in pachytene, leading to massive spermatocyte apoptosis...
October 30, 2017: Nature Structural & Molecular Biology
https://www.readbyqxmd.com/read/29083415/encoding-optical-control-in-lck-kinase-to-quantitatively-investigate-its-activity-in-live-cells
#8
Ardiyanto Liaunardy-Jopeace, Ben L Murton, Mohan Mahesh, Jason W Chin, John R James
LCK is a tyrosine kinase that is essential for initiating T-cell antigen receptor (TCR) signaling. A complete understanding of LCK function is constrained by a paucity of methods to quantitatively study its function within live cells. To address this limitation, we generated LCK*, in which a key active-site lysine is replaced by a photocaged equivalent, using genetic code expansion. This strategy enabled fine temporal and spatial control over kinase activity, thus allowing us to quantify phosphorylation kinetics in situ using biochemical and imaging approaches...
October 30, 2017: Nature Structural & Molecular Biology
https://www.readbyqxmd.com/read/29083414/dissecting-the-telomere-inner-nuclear-membrane-interface-formed-in-meiosis
#9
Devon F Pendlebury, Yasuhiro Fujiwara, Valerie M Tesmer, Eric M Smith, Hiroki Shibuya, Yoshinori Watanabe, Jayakrishnan Nandakumar
Tethering telomeres to the inner nuclear membrane (INM) allows homologous chromosome pairing during meiosis. The meiosis-specific protein TERB1 binds the telomeric protein TRF1 to establish telomere-INM connectivity and is essential for mouse fertility. Here we solve the structure of the human TRF1-TERB1 interface to reveal the structural basis for telomere-INM linkage. Disruption of this interface abrogates binding and compromises telomere-INM attachment in mice. An embedded CDK-phosphorylation site within the TRF1-binding region of TERB1 provides a mechanism for cap exchange, a late-pachytene phenomenon involving the dissociation of the TRF1-TERB1 complex...
October 30, 2017: Nature Structural & Molecular Biology
https://www.readbyqxmd.com/read/29083413/preribosomes-escaping-from-the-nucleus-are-caught-during-translation-by-cytoplasmic-quality-control
#10
Anshuk Sarkar, Matthias Thoms, Clara Barrio-Garcia, Emma Thomson, Dirk Flemming, Roland Beckmann, Ed Hurt
Assembly of fully functional ribosomes is a prerequisite for failsafe translation. This explains why maturing preribosomal subunits have to pass through an array of quality-control checkpoints, including nuclear export, to ensure that only properly assembled ribosomes engage in translation. Despite these safeguards, we found that nuclear pre-60S particles unable to remove a transient structure composed of ITS2 pre-rRNA and associated assembly factors, termed the 'foot', escape to the cytoplasm, where they can join with mature 40S subunits to catalyze protein synthesis...
October 30, 2017: Nature Structural & Molecular Biology
https://www.readbyqxmd.com/read/29058713/dynamic-regulation-of-cd28-conformation-and-signaling-by-charged-lipids-and-ions
#11
Wei Yang, Weiling Pan, Shuokai Chen, Nicola Trendel, Shutan Jiang, Feng Xiao, Manman Xue, Wei Wu, Zeli Peng, Xiaoxi Li, Hongbin Ji, Xiaolong Liu, Hai Jiang, Haopeng Wang, Hongbin Shen, Omer Dushek, Hua Li, Chenqi Xu
CD28 provides an essential costimulatory signal for T cell activation, and its function is critical in antitumor immunity. However, the molecular mechanism of CD28 transmembrane signaling remains elusive. Here we show that the conformation and signaling of CD28 are regulated by two counteractive charged factors, acidic phospholipids and Ca(2+) ions. NMR spectroscopy analyses showed that acidic phospholipids can sequester CD28 signaling motifs within the membrane, thereby limiting CD28 basal signaling. T cell receptor (TCR) activation induced an increase in the local Ca(2+) concentration around CD28, and Ca(2+) directly disrupted CD28-lipid interaction, leading to opening and signaling of CD28...
October 23, 2017: Nature Structural & Molecular Biology
https://www.readbyqxmd.com/read/29058712/molecular-basis-of-lipid-linked-oligosaccharide-recognition-and-processing-by-bacterial-oligosaccharyltransferase
#12
Maja Napiórkowska, Jérémy Boilevin, Tina Sovdat, Tamis Darbre, Jean-Louis Reymond, Markus Aebi, Kaspar P Locher
Oligosaccharyltransferase (OST) is a membrane-integral enzyme that catalyzes the transfer of glycans from lipid-linked oligosaccharides (LLOs) onto asparagine side chains, the first step in protein N-glycosylation. Here, we report the X-ray structure of a single-subunit OST, PglB from Campylobacter lari, trapped in an intermediate state bound to an acceptor peptide and a synthetic LLO analog. The structure reveals the role of the external loop EL5, present in all OST enzymes, in substrate recognition. Whereas the N-terminal half of EL5 binds LLO, the C-terminal half interacts with the acceptor peptide...
October 23, 2017: Nature Structural & Molecular Biology
https://www.readbyqxmd.com/read/29058711/the-helicase-domain-of-pol%C3%AE-counteracts-rpa-to-promote-alt-nhej
#13
Pedro A Mateos-Gomez, Tatiana Kent, Sarah K Deng, Shane McDevitt, Ekaterina Kashkina, Trung M Hoang, Richard T Pomerantz, Agnel Sfeir
Mammalian polymerase theta (Polθ) is a multifunctional enzyme that promotes error-prone DNA repair by alternative nonhomologous end joining (alt-NHEJ). Here we present structure-function analyses that reveal that, in addition to the polymerase domain, Polθ-helicase activity plays a central role during double-strand break (DSB) repair. Our results show that the helicase domain promotes chromosomal translocations by alt-NHEJ in mouse embryonic stem cells and also suppresses CRISPR-Cas9- mediated gene targeting by homologous recombination (HR)...
October 23, 2017: Nature Structural & Molecular Biology
https://www.readbyqxmd.com/read/29058710/dna-binding-by-phf1-prolongs-prc2-residence-time-on-chromatin-and-thereby-promotes-h3k27-methylation
#14
Jeongyoon Choi, Andreas Linus Bachmann, Katharina Tauscher, Christian Benda, Beat Fierz, Jürg Müller
Polycomb repressive complex 2 (PRC2) trimethylates histone H3 at lysine 27 to mark genes for repression. We measured the dynamics of PRC2 binding on recombinant chromatin and free DNA at the single-molecule level using total internal reflection fluorescence (TIRF) microscopy. PRC2 preferentially binds free DNA with multisecond residence time and midnanomolar affinity. PHF1, a PRC2 accessory protein of the Polycomblike family, extends PRC2 residence time on DNA and chromatin. Crystallographic and functional studies reveal that Polycomblike proteins contain a winged-helix domain that binds DNA in a sequence-nonspecific fashion...
October 23, 2017: Nature Structural & Molecular Biology
https://www.readbyqxmd.com/read/29058709/molecular-analysis-of-prc2-recruitment-to-dna-in-chromatin-and-its-inhibition-by-rna
#15
Xueyin Wang, Richard D Paucek, Anne R Gooding, Zachary Z Brown, Eva J Ge, Tom W Muir, Thomas R Cech
Many studies have revealed pathways of epigenetic gene silencing by Polycomb repressive complex 2 (PRC2) in vivo, but understanding the underlying molecular mechanisms requires biochemistry. Here we analyze interactions of reconstituted human PRC2 with nucleosome complexes. Histone modifications, the H3K27M cancer mutation, and inclusion of JARID2 or EZH1 in the PRC2 complex have unexpectedly minor effects on PRC2-nucleosome binding. Instead, protein-free linker DNA dominates the PRC2-nucleosome interaction...
October 23, 2017: Nature Structural & Molecular Biology
https://www.readbyqxmd.com/read/29058708/histone-propionylation-is-a-mark-of-active-chromatin
#16
Adam F Kebede, Anna Nieborak, Lara Zorro Shahidian, Stephanie Le Gras, Florian Richter, Diana Aguilar Gómez, Marijke P Baltissen, Gergo Meszaros, Helena de Fatima Magliarelli, Aaron Taudt, Raphael Margueron, Maria Colomé-Tatché, Romeo Ricci, Sylvain Daujat, Michiel Vermeulen, Gerhard Mittler, Robert Schneider
Histones are highly covalently modified, but the functions of many of these modifications remain unknown. In particular, it is unclear how histone marks are coupled to cellular metabolism and how this coupling affects chromatin architecture. We identified histone H3 Lys14 (H3K14) as a site of propionylation and butyrylation in vivo and carried out the first systematic characterization of histone propionylation. We found that H3K14pr and H3K14bu are deposited by histone acetyltransferases, are preferentially enriched at promoters of active genes and are recognized by acylation-state-specific reader proteins...
October 23, 2017: Nature Structural & Molecular Biology
https://www.readbyqxmd.com/read/29323283/nsmb-at-25
#17
EDITORIAL
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No abstract text is available yet for this article.
January 2018: Nature Structural & Molecular Biology
https://www.readbyqxmd.com/read/29323282/mll2-conveys-transcription-independent-h3k4-trimethylation-in-oocytes
#18
Courtney W Hanna, Aaron Taudt, Jiahao Huang, Lenka Gahurova, Andrea Kranz, Simon Andrews, Wendy Dean, A Francis Stewart, Maria Colomé-Tatché, Gavin Kelsey
Histone 3 K4 trimethylation (depositing H3K4me3 marks) is typically associated with active promoters yet paradoxically occurs at untranscribed domains. Research to delineate the mechanisms of targeting H3K4 methyltransferases is ongoing. The oocyte provides an attractive system to investigate these mechanisms, because extensive H3K4me3 acquisition occurs in nondividing cells. We developed low-input chromatin immunoprecipitation to interrogate H3K4me3, H3K27ac and H3K27me3 marks throughout oogenesis. In nongrowing oocytes, H3K4me3 was restricted to active promoters, but as oogenesis progressed, H3K4me3 accumulated in a transcription-independent manner and was targeted to intergenic regions, putative enhancers and silent H3K27me3-marked promoters...
January 2018: Nature Structural & Molecular Biology
https://www.readbyqxmd.com/read/29323281/bap-sil1-regulates-the-molecular-chaperone-bip-by-coupling-release-of-nucleotide-and-substrate
#19
Mathias Rosam, Daniela Krader, Christina Nickels, Janine Hochmair, Katrin C Back, Ganesh Agam, Anders Barth, Cathleen Zeymer, Jelle Hendrix, Markus Schneider, Iris Antes, Jochen Reinstein, Don C Lamb, Johannes Buchner
BiP is the endoplasmic member of the Hsp70 family. BiP is regulated by several co-chaperones including the nucleotide-exchange factor (NEF) Bap (Sil1 in yeast). Bap is a two-domain protein. The interaction of the Bap C-terminal domain with the BiP ATPase domain is sufficient for its weak NEF activity. However, stimulation of the BiP ATPase activity requires full-length Bap, suggesting a complex interplay of these two factors. Here, single-molecule FRET experiments with mammalian proteins reveal that Bap affects the conformation of both BiP domains, including the lid subdomain, which is important for substrate binding...
January 2018: Nature Structural & Molecular Biology
https://www.readbyqxmd.com/read/29323280/nucleotide-exchange-factors-fes1-and-hspbp1-mimic-substrate-to-release-misfolded-proteins-from-hsp70
#20
Naveen K C Gowda, Jayasankar M Kaimal, Roman Kityk, Chammiran Daniel, Jobst Liebau, Marie Öhman, Matthias P Mayer, Claes Andréasson
Protein quality control depends on the tight regulation of interactions between molecular chaperones and polypeptide substrates. Substrate release from the chaperone Hsp70 is triggered by nucleotide-exchange factors (NEFs) that control folding and degradation fates via poorly understood mechanisms. We found that the armadillo-type NEFs budding yeast Fes1 and its human homolog HspBP1 employ flexible N-terminal release domains (RDs) with substrate-mimicking properties to ensure the efficient release of persistent substrates from Hsp70...
January 2018: Nature Structural & Molecular Biology
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