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  • A consensus model of human apolipoprotein A-I in its monomeric and lipid-free state
    Nat. Struct. Mol. Biol. (IF 12.595) Pub Date : 2017-11-13
    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

    A consensus model of human apolipoprotein A-I in its monomeric and lipid-free state A consensus model of human apolipoprotein A-I in its monomeric and lipid-free state, Published online: 13 November 2017; doi:10.1038/nsmb.3501 NatureArticleSnippet(type=short-summary, markup= Apolipoprotein A-I (apoA-I) is the scaffold protein that is essential for the assembly and function of HDL particles. A structural model for monomeric, lipid-free apoA-I, based on previous and new data, is now presented. , isJats=true)

    更新日期:2017-11-13
  • Programming asynchronous replication in stem cells
    Nat. Struct. Mol. Biol. (IF 12.595) Pub Date : 2017-11-13
    Hagit Masika, Marganit Farago, Merav Hecht, Reba Condiotti, Kirill Makedonski, Yosef Buganim, Tal Burstyn-Cohen, Yehudit Bergman, Howard Cedar

    Programming asynchronous replication in stem cells Programming asynchronous replication in stem cells, Published online: 13 November 2017; doi:10.1038/nsmb.3503 NatureArticleSnippet(type=short-summary, markup= Asynchronous replication-timing patterns undergo programmed switching between maternal and paternal alleles in embryonic and adult stem cells. , isJats=true)

    更新日期:2017-11-13
  • A consensus model of human apolipoprotein A-I in its monomeric and lipid-free state
    Nat. Struct. Mol. Biol. (IF 12.595) Pub Date : 2017-11-13
    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

    A consensus model of human apolipoprotein A-I in its monomeric and lipid-free state A consensus model of human apolipoprotein A-I in its monomeric and lipid-free state, Published online: 13 November 2017; doi:10.1038/nsmb.3501 NatureArticleSnippet(type=short-summary, markup= Apolipoprotein A-I (apoA-I) is the scaffold protein that is essential for the assembly and function of HDL particles. A structural model for monomeric, lipid-free apoA-I, based on previous and new data, is now presented. , isJats=true)

    更新日期:2017-11-13
  • Programming asynchronous replication in stem cells
    Nat. Struct. Mol. Biol. (IF 12.595) Pub Date : 2017-11-13
    Hagit Masika, Marganit Farago, Merav Hecht, Reba Condiotti, Kirill Makedonski, Yosef Buganim, Tal Burstyn-Cohen, Yehudit Bergman, Howard Cedar

    Programming asynchronous replication in stem cells Programming asynchronous replication in stem cells, Published online: 13 November 2017; doi:10.1038/nsmb.3503 NatureArticleSnippet(type=short-summary, markup= Asynchronous replication-timing patterns undergo programmed switching between maternal and paternal alleles in embryonic and adult stem cells. , isJats=true)

    更新日期:2017-11-13
  • Ribosome origami
    Nat. Struct. Mol. Biol. (IF 12.595) Pub Date : 2017-11-07
    Joanna Rorbach, Shintaro Aibara, Alexey Amunts

    Assembly of the small ribosomal subunit from an RNA strand and 33 proteins is an intricate and dynamic process. Two cryo-EM studies now provide insight into a complicated complex of at least 51 trans-factors that act on the preribosomal small subunit to sequentially fold it into a 3D molecular machine.

    更新日期:2017-11-08
  • Ribosome origami
    Nat. Struct. Mol. Biol. (IF 12.595) Pub Date : 2017-11-01
    Joanna Rorbach, Shintaro Aibara, Alexey Amunts

    Assembly of the small ribosomal subunit from an RNA strand and 33 proteins is an intricate and dynamic process. Two cryo-EM studies now provide insight into a complicated complex of at least 51 trans-factors that act on the preribosomal small subunit to sequentially fold it into a 3D molecular machine.

    更新日期:2017-11-08
  • Extrachromosomal telomere repeat DNA is linked to ALT development via cGAS-STING DNA sensing pathway
    Nat. Struct. Mol. Biol. (IF 12.595) Pub Date : 2017-11-06
    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. Notably, the ALT suppressors histone H3.3 and the ATRX–Daxx histone chaperone complex were also required to activate the DNA-sensing pathway. Collectively, our data suggest that the loss of the cGAS-STING pathway may be required to evade ECTR-induced anti-proliferation effects and permit ALT development, and this requirement may be exploited for treatments specific to cancers utilizing the ALT pathway.

    更新日期:2017-11-06
  • TFIIH generates a six-base-pair open complex during RNAP II transcription initiation and start-site scanning
    Nat. Struct. Mol. Biol. (IF 12.595) Pub Date : 2017-11-06
    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. Here, to test models for initial DNA opening and start-site scanning, we measure the DNA-bubble sizes generated by Saccharomyces cerevisiae PICs in real time using single-molecule magnetic tweezers. We show that ATP hydrolysis by Ssl2 opens a 6-base-pair (bp) bubble that grows to 13 bp in the presence of NTPs. These observations support a two-step model wherein ATP-dependent Ssl2 translocation leads to a 6-bp open complex that RNA polymerase II expands via NTP-dependent RNA transcription.

    更新日期:2017-11-06
  • Short poly(A) tails are a conserved feature of highly expressed genes
    Nat. Struct. Mol. Biol. (IF 12.595) Pub Date : 2017-11-06
    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. This attribute appears to be dependent on translational efficiency, as transcripts enriched for optimal codons and ribosome association had the shortest tail sizes, whereas noncoding RNAs retained long tails. Across eukaryotes, short tails were a feature of abundant and well-translated mRNAs. This seems to contradict the dogma that deadenylation induces translational inhibition and mRNA decay and suggests that well-expressed mRNAs accumulate with pruned tails that accommodate a minimal number of poly(A)-binding proteins, which may be ideal for protective and translational functions.

    更新日期:2017-11-06
  • Cryo-EM structures of the human endolysosomal TRPML3 channel in three distinct states
    Nat. Struct. Mol. Biol. (IF 12.595) Pub Date : 2017-11-06
    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. S1 extends into this cap, forming a 'gating rod' that connects directly to a luminal pore loop, which undergoes dramatic conformational changes in response to low pH. S2 extends intracellularly and interacts with several intracellular regions to form a 'gating knob'. These unique structural features, combined with the results of electrophysiological studies, indicate a new mechanism by which luminal pH and other physiological modulators such as PIP2 regulate TRPML3 by changing S1 and S2 conformations.

    更新日期:2017-11-06
  • Extrachromosomal telomere repeat DNA is linked to ALT development via cGAS-STING DNA sensing pathway
    Nat. Struct. Mol. Biol. (IF 12.595) Pub Date : 2017-11-06
    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. Notably, the ALT suppressors histone H3.3 and the ATRX–Daxx histone chaperone complex were also required to activate the DNA-sensing pathway. Collectively, our data suggest that the loss of the cGAS-STING pathway may be required to evade ECTR-induced anti-proliferation effects and permit ALT development, and this requirement may be exploited for treatments specific to cancers utilizing the ALT pathway.

    更新日期:2017-11-06
  • TFIIH generates a six-base-pair open complex during RNAP II transcription initiation and start-site scanning
    Nat. Struct. Mol. Biol. (IF 12.595) Pub Date : 2017-11-06
    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. Here, to test models for initial DNA opening and start-site scanning, we measure the DNA-bubble sizes generated by Saccharomyces cerevisiae PICs in real time using single-molecule magnetic tweezers. We show that ATP hydrolysis by Ssl2 opens a 6-base-pair (bp) bubble that grows to 13 bp in the presence of NTPs. These observations support a two-step model wherein ATP-dependent Ssl2 translocation leads to a 6-bp open complex that RNA polymerase II expands via NTP-dependent RNA transcription.

    更新日期:2017-11-06
  • Short poly(A) tails are a conserved feature of highly expressed genes
    Nat. Struct. Mol. Biol. (IF 12.595) Pub Date : 2017-11-06
    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. This attribute appears to be dependent on translational efficiency, as transcripts enriched for optimal codons and ribosome association had the shortest tail sizes, whereas noncoding RNAs retained long tails. Across eukaryotes, short tails were a feature of abundant and well-translated mRNAs. This seems to contradict the dogma that deadenylation induces translational inhibition and mRNA decay and suggests that well-expressed mRNAs accumulate with pruned tails that accommodate a minimal number of poly(A)-binding proteins, which may be ideal for protective and translational functions.

    更新日期:2017-11-06
  • Cryo-EM structures of the human endolysosomal TRPML3 channel in three distinct states
    Nat. Struct. Mol. Biol. (IF 12.595) Pub Date : 2017-11-06
    Xiaoyuan Zhou, Minghui Li, Deyuan Su, Qi Jia, Huan Li, Xueming Li, Jian Yang

    Cryo-EM structures of the human endolysosomal TRPML3 channel in three distinct statesCryo-EM structures of the human endolysosomal TRPML3 channel in three distinct states, Published online: 06 November 2017; doi:10.1038/nsmb.3502NatureArticleSnippet(type=short-summary, markup=Cryo-EM analyses of human TRPML3 reveal this channel in three different states—closed, agonist-activated and low-pH-inhibited—and suggest mechanisms for regulation., isJats=true)

    更新日期:2017-11-06
  • Telomeric TERB1–TRF1 interaction is crucial for male meiosis
    Nat. Struct. Mol. Biol. (IF 12.595) Pub Date : 2017-10-30
    Juanjuan Long, Chenhui Huang, Yanyan Chen, Ying Zhang, Shaohua Shi, Ligang Wu, Yie Liu, Chengyu Liu, Jian Wu, Ming Lei

    Telomeric TERB1–TRF1 interaction is crucial for male meiosis Nature Structural & Molecular Biology, Published online: 30 October 2017; doi:10.1038/nsmb.3496 Disrupting the interaction between telomere protein TRF1 with meiosis-specific protein TERB1 impairs the pairing of X and Y chromosomes via their telomere-adjacent pseudoautosomal regions in pachytene, leading to spermatocyte apoptosis and male infertility in mice.

    更新日期:2017-10-30
  • Dissecting the telomere–inner nuclear membrane interface formed in meiosis
    Nat. Struct. Mol. Biol. (IF 12.595) Pub Date : 2017-10-30
    Devon F Pendlebury, Yasuhiro Fujiwara, Valerie M Tesmer, Eric M Smith, Hiroki Shibuya, Yoshinori Watanabe, Jayakrishnan Nandakumar

    Dissecting the telomere–inner nuclear membrane interface formed in meiosis Nature Structural & Molecular Biology, Published online: 30 October 2017; doi:10.1038/nsmb.3493 Structural and functional analyses of human TRF1 in complex with meiosis-specific protein TERB1 reveal the basis for telomere tethering to the inner nuclear membrane and offer insight into the mechanism of dissociation in late pachytene.

    更新日期:2017-10-30
  • Preribosomes escaping from the nucleus are caught during translation by cytoplasmic quality control
    Nat. Struct. Mol. Biol. (IF 12.595) Pub Date : 2017-10-30
    Anshuk Sarkar, Matthias Thoms, Clara Barrio-Garcia, Emma Thomson, Dirk Flemming, Roland Beckmann, Ed Hurt

    Preribosomes escaping from the nucleus are caught during translation by cytoplasmic quality control Nature Structural & Molecular Biology, Published online: 30 October 2017; doi:10.1038/nsmb.3495 Abnormal pre-60S particles are able to escape nuclear quality control and join mature 40S subunits to catalyze cytoplasmic protein synthesis, but the resulting translation defects trigger the cytoplasmic surveillance machineries RQC and the Ski-exosome.

    更新日期:2017-10-30
  • Encoding optical control in LCK kinase to quantitatively investigate its activity in live cells
    Nat. Struct. Mol. Biol. (IF 12.595) Pub Date : 2017-10-30
    Ardiyanto Liaunardy-Jopeace, Ben L Murton, Mohan Mahesh, Jason W Chin, John R James

    Encoding optical control in LCK kinase to quantitatively investigate its activity in live cells Nature Structural & Molecular Biology, Published online: 30 October 2017; doi:10.1038/nsmb.3492 Engineering an LCK mutant, in which an active-site lysine is replaced by a photocaged equivalent via genetic code expansion, allows quantitation of phosphorylation kinetics in situ and provides insights into LCK activation dynamics.

    更新日期:2017-10-30
  • Molecular analysis of PRC2 recruitment to DNA in chromatin and its inhibition by RNA
    Nat. Struct. Mol. Biol. (IF 12.595) Pub Date : 2017-10-23
    Xueyin Wang, Richard D Paucek, Anne R Gooding, Zachary Z Brown, Eva J Ge, Tom W Muir, Thomas R Cech

    Molecular analysis of PRC2 recruitment to DNA in chromatin and its inhibition by RNA Nature Structural & Molecular Biology, Published online: 23 October 2017; doi:10.1038/nsmb.3487 Biochemical reconstitution of PRC2 interactions with chromatinized templates demonstrates that protein-free linker DNA dominates the PRC2-nucleosome interaction, while RNA inhibits binding.

    更新日期:2017-10-30
  • Molecular basis of lipid-linked oligosaccharide recognition and processing by bacterial oligosaccharyltransferase
    Nat. Struct. Mol. Biol. (IF 12.595) Pub Date : 2017-10-23
    Maja Napiórkowska, Jérémy Boilevin, Tina Sovdat, Tamis Darbre, Jean-Louis Reymond, Markus Aebi, Kaspar P Locher

    Molecular basis of lipid-linked oligosaccharide recognition and processing by bacterial oligosaccharyltransferase Nature Structural & Molecular Biology, Published online: 23 October 2017; doi:10.1038/nsmb.3491 The crystal structure of the single-subunit oligosaccharyltransferase PglB in complex with acceptor peptide and a synthetic lipid-linked oligosaccharide analog reveals a key intermediate in the reaction mechanism.

    更新日期:2017-10-30
  • Dynamic regulation of CD28 conformation and signaling by charged lipids and ions
    Nat. Struct. Mol. Biol. (IF 12.595) Pub Date : 2017-10-23
    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

    Dynamic regulation of CD28 conformation and signaling by charged lipids and ions Nature Structural & Molecular Biology, Published online: 23 October 2017; doi:10.1038/nsmb.3489 CD28 signaling motifs are sequestered within the membrane via interactions with phospholipids. TCR activation increases the local Ca2+ concentration, which disrupts CD28-lipid interactions.

    更新日期:2017-10-30
  • Histone propionylation is a mark of active chromatin
    Nat. Struct. Mol. Biol. (IF 12.595) Pub Date : 2017-10-23
    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

    Histone propionylation is a mark of active chromatin Nature Structural & Molecular Biology, Published online: 23 October 2017; doi:10.1038/nsmb.3490 Histone H3 lysine 14 is propionylated and butyrylated in vivo in a metabolic-state-dependent manner and these modifications promote high levels of transcription.

    更新日期:2017-10-30
  • Telomeric TERB1–TRF1 interaction is crucial for male meiosis
    Nat. Struct. Mol. Biol. (IF 12.595) Pub Date : 2017-10-30
    Juanjuan Long, Chenhui Huang, Yanyan Chen, Ying Zhang, Shaohua Shi, Ligang Wu, Yie Liu, Chengyu Liu, Jian Wu, Ming Lei

    Telomeric TERB1–TRF1 interaction is crucial for male meiosis Nature Structural & Molecular Biology, Published online: 30 October 2017; doi:10.1038/nsmb.3496 Disrupting the interaction between telomere protein TRF1 with meiosis-specific protein TERB1 impairs the pairing of X and Y chromosomes via their telomere-adjacent pseudoautosomal regions in pachytene, leading to spermatocyte apoptosis and male infertility in mice.

    更新日期:2017-10-30
  • Dissecting the telomere–inner nuclear membrane interface formed in meiosis
    Nat. Struct. Mol. Biol. (IF 12.595) Pub Date : 2017-10-30
    Devon F Pendlebury, Yasuhiro Fujiwara, Valerie M Tesmer, Eric M Smith, Hiroki Shibuya, Yoshinori Watanabe, Jayakrishnan Nandakumar

    Dissecting the telomere–inner nuclear membrane interface formed in meiosis Nature Structural & Molecular Biology, Published online: 30 October 2017; doi:10.1038/nsmb.3493 Structural and functional analyses of human TRF1 in complex with meiosis-specific protein TERB1 reveal the basis for telomere tethering to the inner nuclear membrane and offer insight into the mechanism of dissociation in late pachytene.

    更新日期:2017-10-30
  • Preribosomes escaping from the nucleus are caught during translation by cytoplasmic quality control
    Nat. Struct. Mol. Biol. (IF 12.595) Pub Date : 2017-10-30
    Anshuk Sarkar, Matthias Thoms, Clara Barrio-Garcia, Emma Thomson, Dirk Flemming, Roland Beckmann, Ed Hurt

    Preribosomes escaping from the nucleus are caught during translation by cytoplasmic quality control Nature Structural & Molecular Biology, Published online: 30 October 2017; doi:10.1038/nsmb.3495 Abnormal pre-60S particles are able to escape nuclear quality control and join mature 40S subunits to catalyze cytoplasmic protein synthesis, but the resulting translation defects trigger the cytoplasmic surveillance machineries RQC and the Ski-exosome.

    更新日期:2017-10-30
  • Encoding optical control in LCK kinase to quantitatively investigate its activity in live cells
    Nat. Struct. Mol. Biol. (IF 12.595) Pub Date : 2017-10-30
    Ardiyanto Liaunardy-Jopeace, Ben L Murton, Mohan Mahesh, Jason W Chin, John R James

    Encoding optical control in LCK kinase to quantitatively investigate its activity in live cells Nature Structural & Molecular Biology, Published online: 30 October 2017; doi:10.1038/nsmb.3492 Engineering an LCK mutant, in which an active-site lysine is replaced by a photocaged equivalent via genetic code expansion, allows quantitation of phosphorylation kinetics in situ and provides insights into LCK activation dynamics.

    更新日期:2017-10-30
  • Molecular analysis of PRC2 recruitment to DNA in chromatin and its inhibition by RNA
    Nat. Struct. Mol. Biol. (IF 12.595) Pub Date : 2017-10-23
    Xueyin Wang, Richard D Paucek, Anne R Gooding, Zachary Z Brown, Eva J Ge, Tom W Muir, Thomas R Cech

    Molecular analysis of PRC2 recruitment to DNA in chromatin and its inhibition by RNA Nature Structural & Molecular Biology, Published online: 23 October 2017; doi:10.1038/nsmb.3487 Biochemical reconstitution of PRC2 interactions with chromatinized templates demonstrates that protein-free linker DNA dominates the PRC2-nucleosome interaction, while RNA inhibits binding.

    更新日期:2017-10-30
  • Molecular basis of lipid-linked oligosaccharide recognition and processing by bacterial oligosaccharyltransferase
    Nat. Struct. Mol. Biol. (IF 12.595) Pub Date : 2017-10-23
    Maja Napiórkowska, Jérémy Boilevin, Tina Sovdat, Tamis Darbre, Jean-Louis Reymond, Markus Aebi, Kaspar P Locher

    Molecular basis of lipid-linked oligosaccharide recognition and processing by bacterial oligosaccharyltransferase Nature Structural & Molecular Biology, Published online: 23 October 2017; doi:10.1038/nsmb.3491 The crystal structure of the single-subunit oligosaccharyltransferase PglB in complex with acceptor peptide and a synthetic lipid-linked oligosaccharide analog reveals a key intermediate in the reaction mechanism.

    更新日期:2017-10-30
  • Dynamic regulation of CD28 conformation and signaling by charged lipids and ions
    Nat. Struct. Mol. Biol. (IF 12.595) Pub Date : 2017-10-23
    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

    Dynamic regulation of CD28 conformation and signaling by charged lipids and ions Nature Structural & Molecular Biology, Published online: 23 October 2017; doi:10.1038/nsmb.3489 CD28 signaling motifs are sequestered within the membrane via interactions with phospholipids. TCR activation increases the local Ca2+ concentration, which disrupts CD28-lipid interactions.

    更新日期:2017-10-30
  • Histone propionylation is a mark of active chromatin
    Nat. Struct. Mol. Biol. (IF 12.595) Pub Date : 2017-10-23
    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

    Histone propionylation is a mark of active chromatin Nature Structural & Molecular Biology, Published online: 23 October 2017; doi:10.1038/nsmb.3490 Histone H3 lysine 14 is propionylated and butyrylated in vivo in a metabolic-state-dependent manner and these modifications promote high levels of transcription.

    更新日期:2017-10-30
  • Class 2 CRISPR–Cas RNA-guided endonucleases: Swiss Army knives of genome editing
    Nat. Struct. Mol. Biol. (IF 12.595) Pub Date : 
    Stefano Stella, Pablo Alcón, Guillermo Montoya

    Class 2 CRISPR–Cas RNA-guided endonucleases: Swiss Army knives of genome editing Nature Structural & Molecular Biology, Published online: 16 October 2017; doi:10.1038/nsmb.3486 This review highlights recent mechanistic insights into the CRISPR class 2 type V enzymes Cpf1 and C2c1, which are crucial for improving these genome engineering tools and expanding the genomic editing space.

    更新日期:2017-10-16
  • Class 2 CRISPR–Cas RNA-guided endonucleases: Swiss Army knives of genome editing
    Nat. Struct. Mol. Biol. (IF 12.595) Pub Date : 
    Stefano Stella, Pablo Alcón, Guillermo Montoya

    Class 2 CRISPR–Cas RNA-guided endonucleases: Swiss Army knives of genome editing Nature Structural & Molecular Biology, Published online: 16 October 2017; doi:10.1038/nsmb.3486 This review highlights recent mechanistic insights into the CRISPR class 2 type V enzymes Cpf1 and C2c1, which are crucial for improving these genome engineering tools and expanding the genomic editing space.

    更新日期:2017-10-16
  • MacroH2A1.1 regulates mitochondrial respiration by limiting nuclear NAD+ consumption
    Nat. Struct. Mol. Biol. (IF 12.595) Pub Date : 
    Melanija Posavec Marjanović, Sarah Hurtado-Bagès, Maximilian Lassi, Vanesa Valero, Roberto Malinverni, Hélène Delage, Miriam Navarro, David Corujo, Iva Guberovic, Julien Douet, Pau Gama-Perez, Pablo M Garcia-Roves, Ivan Ahel, Andreas G Ladurner, Oscar Yanes, Philippe Bouvet, Mònica Suelves, Raffaele Teperino, J Andrew Pospisilik, Marcus Buschbeck

    Histone variants are structural components of eukaryotic chromatin that can replace replication-coupled histones in the nucleosome. The histone variant macroH2A1.1 contains a macrodomain capable of binding NAD+-derived metabolites. Here we report that macroH2A1.1 is rapidly induced during myogenic differentiation through a switch in alternative splicing, and that myotubes that lack macroH2A1.1 have a defect in mitochondrial respiratory capacity. We found that the metabolite-binding macrodomain was essential for sustained optimal mitochondrial function but dispensable for gene regulation. Through direct binding, macroH2A1.1 inhibits basal poly-ADP ribose polymerase 1 (PARP-1) activity and thus reduces nuclear NAD+ consumption. The resultant accumulation of the NAD+ precursor NMN allows for maintenance of mitochondrial NAD+ pools that are critical for respiration. Our data indicate that macroH2A1.1-containing chromatin regulates mitochondrial respiration by limiting nuclear NAD+ consumption and establishing a buffer of NAD+ precursors in differentiated cells.

    更新日期:2017-10-11
  • A structural model for microtubule minus-end recognition and protection by CAMSAP proteins
    Nat. Struct. Mol. Biol. (IF 12.595) Pub Date : 
    Joseph Atherton, Kai Jiang, Marcel M Stangier, Yanzhang Luo, Shasha Hua, Klaartje Houben, Jolien J E van Hooff, Agnel-Praveen Joseph, Guido Scarabelli, Barry J Grant, Anthony J Roberts, Maya Topf, Michel O Steinmetz, Marc Baldus, Carolyn A Moores, Anna Akhmanova

    CAMSAP and Patronin family members regulate microtubule minus-end stability and localization and thus organize noncentrosomal microtubule networks, which are essential for cell division, polarization and differentiation. Here, we found that the CAMSAP C-terminal CKK domain is widely present among eukaryotes and autonomously recognizes microtubule minus ends. Through a combination of structural approaches, we uncovered how mammalian CKK binds between two tubulin dimers at the interprotofilament interface on the outer microtubule surface. In vitro reconstitution assays combined with high-resolution fluorescence microscopy and cryo-electron tomography suggested that CKK preferentially associates with the transition zone between curved protofilaments and the regular microtubule lattice. We propose that minus-end-specific features of the interprotofilament interface at this site serve as the basis for CKK's minus-end preference. The steric clash between microtubule-bound CKK and kinesin motors explains how CKK protects microtubule minus ends against kinesin-13-induced depolymerization and thus controls the stability of free microtubule minus ends.

    更新日期:2017-10-11
  • Architectural alterations of the fission yeast genome during the cell cycle
    Nat. Struct. Mol. Biol. (IF 12.595) Pub Date : 
    Hideki Tanizawa, Kyoung-Dong Kim, Osamu Iwasaki, Ken-ichi Noma

    Eukaryotic genomes are highly ordered through various mechanisms, including topologically associating domain (TAD) organization. We employed an in situ Hi-C approach to follow the 3D organization of the fission yeast genome during the cell cycle. We demonstrate that during mitosis, large domains of 300 kb–1 Mb are formed by condensin. This mitotic domain organization does not suddenly dissolve, but gradually diminishes until the next mitosis. By contrast, small domains of 30–40 kb that are formed by cohesin are relatively stable across the cell cycle. Condensin and cohesin mediate long- and short-range contacts, respectively, by bridging their binding sites, thereby forming the large and small domains. These domains are inversely regulated during the cell cycle but assemble independently. Our study describes the chromosomal oscillation between the formation and decay phases of the large and small domains, and we predict that the condensin-mediated domains serve as chromosomal compaction units.

    更新日期:2017-10-11
  • Structural basis for GABAA receptor potentiation by neurosteroids
    Nat. Struct. Mol. Biol. (IF 12.595) Pub Date : 
    Paul S Miller, Suzanne Scott, Simonas Masiulis, Luigi De Colibus, Els Pardon, Jan Steyaert, A Radu Aricescu

    Type A γ-aminobutyric acid receptors (GABAARs) are the principal mediators of inhibitory neurotransmission in the human brain. Endogenous neurosteroids interact with GABAARs to regulate acute and chronic anxiety and are potent sedative, analgesic, anticonvulsant and anesthetic agents. Their mode of binding and mechanism of receptor potentiation, however, remain unknown. Here we report crystal structures of a chimeric GABAAR construct in apo and pregnanolone-bound states. The neurosteroid-binding site is mechanically coupled to the helices lining the ion channel pore and modulates the desensitization-gate conformation. We demonstrate that the equivalent site is responsible for physiological, heteromeric GABAAR potentiation and explain the contrasting modulatory properties of 3a versus 3b neurosteroid epimers. These results illustrate how peripheral lipid ligands can regulate the desensitization gate of GABAARs, a process of broad relevance to pentameric ligand-gated ion channels.

    更新日期:2017-10-11
  • A glimpse into the C-type-inactivated state for a Potassium Channel
    Nat. Struct. Mol. Biol. (IF 12.595) Pub Date : 
    Francis I Valiyaveetil

    A glimpse into the C-type-inactivated state for a Potassium Channel Nature Structural & Molecular Biology, Published online: 5 October 2017; doi:10.1038/nsmb.3480 C-type inactivation is a process by which ion flux through a voltage-gated K+ channel is regulated at the selectivity filter. A recent structure of the Kv1.2 channel provides a view into the structural changes of the selectivity filter during C-type inactivation.

    更新日期:2017-10-11
  • Fine-tuning PERK signaling to control cell fate under stress
    Nat. Struct. Mol. Biol. (IF 12.595) Pub Date : 
    Hery Urra, Claudio Hetz

    Fine-tuning PERK signaling to control cell fate under stress Nature Structural & Molecular Biology, Published online: 5 October 2017; doi:10.1038/nsmb.3478 PERK is a major sensor of the unfolded protein response controlling cell fate under endoplasmic reticulum (ER) stress. A new study reveals an additional step for optimal PERK signaling, involving the binding of CNPY2 to PERK's luminal domain. The PERK–CNPY2 axis was shown to enhance cell death under ER stress in vivo influence liver disease.

    更新日期:2017-10-11
  • Cryo-electron microscopy snapshots of the spliceosome: structural insights into a dynamic ribonucleoprotein machine
    Nat. Struct. Mol. Biol. (IF 12.595) Pub Date : 
    Sebastian M Fica, Kiyoshi Nagai

    The spliceosome excises introns from pre-messenger RNAs using an RNA-based active site that is cradled by a dynamic protein scaffold. A recent revolution in cryo-electron microscopy (cryo-EM) has led to near-atomic-resolution structures of key spliceosome complexes that provide insight into the mechanism of activation, splice site positioning, catalysis, protein rearrangements and ATPase-mediated dynamics of the active site. The cryo-EM structures rationalize decades of observations from genetic and biochemical studies and provide a molecular framework for future functional studies.

    更新日期:2017-10-11
  • Insights into a PCSK9 structural groove: a harbinger of new drugs to reduce LDL-cholesterol
    Nat. Struct. Mol. Biol. (IF 12.595) Pub Date : 
    Nabil G Seidah

    Insights into a PCSK9 structural groove: a harbinger of new drugs to reduce LDL-cholesterol Nature Structural & Molecular Biology, Published online: 5 October 2017; doi:10.1038/nsmb.3471 PCSK9 enhances LDL cholesterol (LDL-c) levels by escorting the liver LDL receptor (LDLR) to endosomes and lysosomes for degradation. PCSK9 monoclonal antibodies and RNA-antisense formulations are effective in reducing LDL cholesterol in patients. The recent structural identification of a novel pocket in PCSK9 paves the way to the future development of orally active small-molecule hypocholesterolemic drugs.

    更新日期:2017-10-11
  • MacroH2A1.1 regulates mitochondrial respiration by limiting nuclear NAD+ consumption
    Nat. Struct. Mol. Biol. (IF 12.595) Pub Date : 
    Melanija Posavec Marjanović, Sarah Hurtado-Bagès, Maximilian Lassi, Vanesa Valero, Roberto Malinverni, Hélène Delage, Miriam Navarro, David Corujo, Iva Guberovic, Julien Douet, Pau Gama-Perez, Pablo M Garcia-Roves, Ivan Ahel, Andreas G Ladurner, Oscar Yanes, Philippe Bouvet, Mònica Suelves, Raffaele Teperino, J Andrew Pospisilik, Marcus Buschbeck

    Histone variants are structural components of eukaryotic chromatin that can replace replication-coupled histones in the nucleosome. The histone variant macroH2A1.1 contains a macrodomain capable of binding NAD+-derived metabolites. Here we report that macroH2A1.1 is rapidly induced during myogenic differentiation through a switch in alternative splicing, and that myotubes that lack macroH2A1.1 have a defect in mitochondrial respiratory capacity. We found that the metabolite-binding macrodomain was essential for sustained optimal mitochondrial function but dispensable for gene regulation. Through direct binding, macroH2A1.1 inhibits basal poly-ADP ribose polymerase 1 (PARP-1) activity and thus reduces nuclear NAD+ consumption. The resultant accumulation of the NAD+ precursor NMN allows for maintenance of mitochondrial NAD+ pools that are critical for respiration. Our data indicate that macroH2A1.1-containing chromatin regulates mitochondrial respiration by limiting nuclear NAD+ consumption and establishing a buffer of NAD+ precursors in differentiated cells.

    更新日期:2017-10-11
  • A structural model for microtubule minus-end recognition and protection by CAMSAP proteins
    Nat. Struct. Mol. Biol. (IF 12.595) Pub Date : 
    Joseph Atherton, Kai Jiang, Marcel M Stangier, Yanzhang Luo, Shasha Hua, Klaartje Houben, Jolien J E van Hooff, Agnel-Praveen Joseph, Guido Scarabelli, Barry J Grant, Anthony J Roberts, Maya Topf, Michel O Steinmetz, Marc Baldus, Carolyn A Moores, Anna Akhmanova

    CAMSAP and Patronin family members regulate microtubule minus-end stability and localization and thus organize noncentrosomal microtubule networks, which are essential for cell division, polarization and differentiation. Here, we found that the CAMSAP C-terminal CKK domain is widely present among eukaryotes and autonomously recognizes microtubule minus ends. Through a combination of structural approaches, we uncovered how mammalian CKK binds between two tubulin dimers at the interprotofilament interface on the outer microtubule surface. In vitro reconstitution assays combined with high-resolution fluorescence microscopy and cryo-electron tomography suggested that CKK preferentially associates with the transition zone between curved protofilaments and the regular microtubule lattice. We propose that minus-end-specific features of the interprotofilament interface at this site serve as the basis for CKK's minus-end preference. The steric clash between microtubule-bound CKK and kinesin motors explains how CKK protects microtubule minus ends against kinesin-13-induced depolymerization and thus controls the stability of free microtubule minus ends.

    更新日期:2017-10-11
  • Architectural alterations of the fission yeast genome during the cell cycle
    Nat. Struct. Mol. Biol. (IF 12.595) Pub Date : 
    Hideki Tanizawa, Kyoung-Dong Kim, Osamu Iwasaki, Ken-ichi Noma

    Eukaryotic genomes are highly ordered through various mechanisms, including topologically associating domain (TAD) organization. We employed an in situ Hi-C approach to follow the 3D organization of the fission yeast genome during the cell cycle. We demonstrate that during mitosis, large domains of 300 kb–1 Mb are formed by condensin. This mitotic domain organization does not suddenly dissolve, but gradually diminishes until the next mitosis. By contrast, small domains of 30–40 kb that are formed by cohesin are relatively stable across the cell cycle. Condensin and cohesin mediate long- and short-range contacts, respectively, by bridging their binding sites, thereby forming the large and small domains. These domains are inversely regulated during the cell cycle but assemble independently. Our study describes the chromosomal oscillation between the formation and decay phases of the large and small domains, and we predict that the condensin-mediated domains serve as chromosomal compaction units.

    更新日期:2017-10-11
  • Structural basis for GABAA receptor potentiation by neurosteroids
    Nat. Struct. Mol. Biol. (IF 12.595) Pub Date : 
    Paul S Miller, Suzanne Scott, Simonas Masiulis, Luigi De Colibus, Els Pardon, Jan Steyaert, A Radu Aricescu

    Type A γ-aminobutyric acid receptors (GABAARs) are the principal mediators of inhibitory neurotransmission in the human brain. Endogenous neurosteroids interact with GABAARs to regulate acute and chronic anxiety and are potent sedative, analgesic, anticonvulsant and anesthetic agents. Their mode of binding and mechanism of receptor potentiation, however, remain unknown. Here we report crystal structures of a chimeric GABAAR construct in apo and pregnanolone-bound states. The neurosteroid-binding site is mechanically coupled to the helices lining the ion channel pore and modulates the desensitization-gate conformation. We demonstrate that the equivalent site is responsible for physiological, heteromeric GABAAR potentiation and explain the contrasting modulatory properties of 3a versus 3b neurosteroid epimers. These results illustrate how peripheral lipid ligands can regulate the desensitization gate of GABAARs, a process of broad relevance to pentameric ligand-gated ion channels.

    更新日期:2017-10-11
  • A glimpse into the C-type-inactivated state for a Potassium Channel
    Nat. Struct. Mol. Biol. (IF 12.595) Pub Date : 
    Francis I Valiyaveetil

    A glimpse into the C-type-inactivated state for a Potassium Channel Nature Structural & Molecular Biology, Published online: 5 October 2017; doi:10.1038/nsmb.3480 C-type inactivation is a process by which ion flux through a voltage-gated K+ channel is regulated at the selectivity filter. A recent structure of the Kv1.2 channel provides a view into the structural changes of the selectivity filter during C-type inactivation.

    更新日期:2017-10-11
  • Fine-tuning PERK signaling to control cell fate under stress
    Nat. Struct. Mol. Biol. (IF 12.595) Pub Date : 
    Hery Urra, Claudio Hetz

    Fine-tuning PERK signaling to control cell fate under stress Nature Structural & Molecular Biology, Published online: 5 October 2017; doi:10.1038/nsmb.3478 PERK is a major sensor of the unfolded protein response controlling cell fate under endoplasmic reticulum (ER) stress. A new study reveals an additional step for optimal PERK signaling, involving the binding of CNPY2 to PERK's luminal domain. The PERK–CNPY2 axis was shown to enhance cell death under ER stress in vivo influence liver disease.

    更新日期:2017-10-11
  • Cryo-electron microscopy snapshots of the spliceosome: structural insights into a dynamic ribonucleoprotein machine
    Nat. Struct. Mol. Biol. (IF 12.595) Pub Date : 
    Sebastian M Fica, Kiyoshi Nagai

    The spliceosome excises introns from pre-messenger RNAs using an RNA-based active site that is cradled by a dynamic protein scaffold. A recent revolution in cryo-electron microscopy (cryo-EM) has led to near-atomic-resolution structures of key spliceosome complexes that provide insight into the mechanism of activation, splice site positioning, catalysis, protein rearrangements and ATPase-mediated dynamics of the active site. The cryo-EM structures rationalize decades of observations from genetic and biochemical studies and provide a molecular framework for future functional studies.

    更新日期:2017-10-11
  • Insights into a PCSK9 structural groove: a harbinger of new drugs to reduce LDL-cholesterol
    Nat. Struct. Mol. Biol. (IF 12.595) Pub Date : 
    Nabil G Seidah

    Insights into a PCSK9 structural groove: a harbinger of new drugs to reduce LDL-cholesterol Nature Structural & Molecular Biology, Published online: 5 October 2017; doi:10.1038/nsmb.3471 PCSK9 enhances LDL cholesterol (LDL-c) levels by escorting the liver LDL receptor (LDLR) to endosomes and lysosomes for degradation. PCSK9 monoclonal antibodies and RNA-antisense formulations are effective in reducing LDL cholesterol in patients. The recent structural identification of a novel pocket in PCSK9 paves the way to the future development of orally active small-molecule hypocholesterolemic drugs.

    更新日期:2017-10-11
  • Structural basis for specific cleavage of Lys6-linked polyubiquitin chains by USP30
    Nat. Struct. Mol. Biol. (IF 12.595) Pub Date : 
    Yusuke Sato, Kei Okatsu, Yasushi Saeki, Koji Yamano, Noriyuki Matsuda, Ai Kaiho, Atsushi Yamagata, Sakurako Goto-Ito, Minoru Ishikawa, Yuichi Hashimoto, Keiji Tanaka, Shuya Fukai

    Parkin ubiquitin (Ub) ligase (also known as PARK2) ubiquitinates damaged mitochondria for their clearance and quality control. USP30 deubiquitinase opposes parkin-mediated Ub-chain formation on mitochondria by preferentially cleaving Lys6-linked Ub chains. Here, we report the crystal structure of zebrafish USP30 in complex with a Lys6-linked diubiquitin (diUb or Ub2) at 1.87-Å resolution. The distal Ub-recognition mechanism of USP30 is similar to those of other USP family members, whereas Phe4 and Thr12 of the proximal Ub are recognized by a USP30-specific surface. Structure-based mutagenesis showed that the interface with the proximal Ub is critical for the specific cleavage of Lys6-linked Ub chains, together with the noncanonical catalytic triad composed of Cys-His-Ser. The structural findings presented here reveal a mechanism for Lys6-linkage-specific deubiquitination.

    更新日期:2017-09-25
  • Mechanism and regulation of the Lys6-selective deubiquitinase USP30
    Nat. Struct. Mol. Biol. (IF 12.595) Pub Date : 
    Malte Gersch, Christina Gladkova, Alexander F Schubert, Martin A Michel, Sarah Maslen, David Komander

    Damaged mitochondria undergo mitophagy, a specialized form of autophagy that is initiated by the protein kinase PINK1 and the ubiquitin E3 ligase Parkin. Ubiquitin-specific protease USP30 antagonizes Parkin-mediated ubiquitination events on mitochondria and is a key negative regulator of mitophagy. Parkin and USP30 both show a preference for assembly or disassembly, respectively, of Lys6-linked polyubiquitin, a chain type that has not been well studied. Here we report crystal structures of human USP30 bound to monoubiquitin and Lys6-linked diubiquitin, which explain how USP30 achieves Lys6-linkage preference through unique ubiquitin binding interfaces. We assess the interplay between USP30, PINK1 and Parkin and show that distally phosphorylated ubiquitin chains impair USP30 activity. Lys6-linkage-specific affimers identify numerous mitochondrial substrates for this modification, and we show that USP30 regulates Lys6-polyubiquitinated TOM20. Our work provides insights into the architecture, activity and regulation of USP30, which will aid drug design against this and related enzymes.

    更新日期:2017-09-25
  • Atomic view of the energy landscape in the allosteric regulation of Abl kinase
    Nat. Struct. Mol. Biol. (IF 12.595) Pub Date : 
    Tamjeed Saleh, Paolo Rossi, Charalampos G Kalodimos

    The activity of protein kinases is often regulated in an intramolecular fashion by signaling domains, which feature several phosphorylation or protein-docking sites. How kinases integrate such distinct binding and signaling events to regulate their activities is unclear, especially in quantitative terms. We used NMR spectroscopy to show how structural elements within the Abl regulatory module (RM) synergistically generate a multilayered allosteric mechanism that enables Abl kinase to function as a finely tuned switch. We dissected the structure and energetics of the regulatory mechanism to precisely measure the effects of various activating or inhibiting stimuli on Abl kinase activity. The data provide a mechanistic basis explaining genetic observations and reveal a previously unknown activator region within Abl. Our findings show that drug-resistance mutations in the Abl RM exert their allosteric effect by promoting the activated state of Abl and not by decreasing the drug affinity for the kinase.

    更新日期:2017-09-25
  • The complete structure of the small-subunit processome
    Nat. Struct. Mol. Biol. (IF 12.595) Pub Date : 
    Jonas Barandun, Malik Chaker-Margot, Mirjam Hunziker, Kelly R Molloy, Brian T Chait, Sebastian Klinge

    The small-subunit processome represents the earliest stable precursor of the eukaryotic small ribosomal subunit. Here we present the cryo-EM structure of the Saccharomyces cerevisiae small-subunit processome at an overall resolution of 3.8 Å, which provides an essentially complete near-atomic model of this assembly. In this nucleolar superstructure, 51 ribosome-assembly factors and two RNAs encapsulate the 18S rRNA precursor and 15 ribosomal proteins in a state that precedes pre-rRNA cleavage at site A1. Extended flexible proteins are employed to connect distant sites in this particle. Molecular mimicry and steric hindrance, as well as protein- and RNA-mediated RNA remodeling, are used in a concerted fashion to prevent the premature formation of the central pseudoknot and its surrounding elements within the small ribosomal subunit.

    更新日期:2017-09-25
  • Structural basis for specific cleavage of Lys6-linked polyubiquitin chains by USP30
    Nat. Struct. Mol. Biol. (IF 12.595) Pub Date : 
    Yusuke Sato, Kei Okatsu, Yasushi Saeki, Koji Yamano, Noriyuki Matsuda, Ai Kaiho, Atsushi Yamagata, Sakurako Goto-Ito, Minoru Ishikawa, Yuichi Hashimoto, Keiji Tanaka, Shuya Fukai

    Parkin ubiquitin (Ub) ligase (also known as PARK2) ubiquitinates damaged mitochondria for their clearance and quality control. USP30 deubiquitinase opposes parkin-mediated Ub-chain formation on mitochondria by preferentially cleaving Lys6-linked Ub chains. Here, we report the crystal structure of zebrafish USP30 in complex with a Lys6-linked diubiquitin (diUb or Ub2) at 1.87-Å resolution. The distal Ub-recognition mechanism of USP30 is similar to those of other USP family members, whereas Phe4 and Thr12 of the proximal Ub are recognized by a USP30-specific surface. Structure-based mutagenesis showed that the interface with the proximal Ub is critical for the specific cleavage of Lys6-linked Ub chains, together with the noncanonical catalytic triad composed of Cys-His-Ser. The structural findings presented here reveal a mechanism for Lys6-linkage-specific deubiquitination.

    更新日期:2017-09-25
  • Mechanism and regulation of the Lys6-selective deubiquitinase USP30
    Nat. Struct. Mol. Biol. (IF 12.595) Pub Date : 
    Malte Gersch, Christina Gladkova, Alexander F Schubert, Martin A Michel, Sarah Maslen, David Komander

    Damaged mitochondria undergo mitophagy, a specialized form of autophagy that is initiated by the protein kinase PINK1 and the ubiquitin E3 ligase Parkin. Ubiquitin-specific protease USP30 antagonizes Parkin-mediated ubiquitination events on mitochondria and is a key negative regulator of mitophagy. Parkin and USP30 both show a preference for assembly or disassembly, respectively, of Lys6-linked polyubiquitin, a chain type that has not been well studied. Here we report crystal structures of human USP30 bound to monoubiquitin and Lys6-linked diubiquitin, which explain how USP30 achieves Lys6-linkage preference through unique ubiquitin binding interfaces. We assess the interplay between USP30, PINK1 and Parkin and show that distally phosphorylated ubiquitin chains impair USP30 activity. Lys6-linkage-specific affimers identify numerous mitochondrial substrates for this modification, and we show that USP30 regulates Lys6-polyubiquitinated TOM20. Our work provides insights into the architecture, activity and regulation of USP30, which will aid drug design against this and related enzymes.

    更新日期:2017-09-25
  • Atomic view of the energy landscape in the allosteric regulation of Abl kinase
    Nat. Struct. Mol. Biol. (IF 12.595) Pub Date : 
    Tamjeed Saleh, Paolo Rossi, Charalampos G Kalodimos

    The activity of protein kinases is often regulated in an intramolecular fashion by signaling domains, which feature several phosphorylation or protein-docking sites. How kinases integrate such distinct binding and signaling events to regulate their activities is unclear, especially in quantitative terms. We used NMR spectroscopy to show how structural elements within the Abl regulatory module (RM) synergistically generate a multilayered allosteric mechanism that enables Abl kinase to function as a finely tuned switch. We dissected the structure and energetics of the regulatory mechanism to precisely measure the effects of various activating or inhibiting stimuli on Abl kinase activity. The data provide a mechanistic basis explaining genetic observations and reveal a previously unknown activator region within Abl. Our findings show that drug-resistance mutations in the Abl RM exert their allosteric effect by promoting the activated state of Abl and not by decreasing the drug affinity for the kinase.

    更新日期:2017-09-25
  • The complete structure of the small-subunit processome
    Nat. Struct. Mol. Biol. (IF 12.595) Pub Date : 
    Jonas Barandun, Malik Chaker-Margot, Mirjam Hunziker, Kelly R Molloy, Brian T Chait, Sebastian Klinge

    The small-subunit processome represents the earliest stable precursor of the eukaryotic small ribosomal subunit. Here we present the cryo-EM structure of the Saccharomyces cerevisiae small-subunit processome at an overall resolution of 3.8 Å, which provides an essentially complete near-atomic model of this assembly. In this nucleolar superstructure, 51 ribosome-assembly factors and two RNAs encapsulate the 18S rRNA precursor and 15 ribosomal proteins in a state that precedes pre-rRNA cleavage at site A1. Extended flexible proteins are employed to connect distant sites in this particle. Molecular mimicry and steric hindrance, as well as protein- and RNA-mediated RNA remodeling, are used in a concerted fashion to prevent the premature formation of the central pseudoknot and its surrounding elements within the small ribosomal subunit.

    更新日期:2017-09-25
  • Structure of a transcribing RNA polymerase II–DSIF complex reveals a multidentate DNA–RNA clamp
    Nat. Struct. Mol. Biol. (IF 12.595) Pub Date : 2017-09-11
    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. The mobile C-terminal region of DSIF is located near exiting RNA, where it can recruit factors for RNA processing. The structure provides insight into the roles of DSIF during mRNA synthesis.

    更新日期:2017-09-15
  • Structures of the human mitochondrial ribosome in native states of assembly
    Nat. Struct. Mol. Biol. (IF 12.595) Pub Date : 2017-09-11
    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. Comparison of the structures reveals insights into the timing of rRNA folding and protein incorporation during the final steps of ribosomal maturation and the evolutionary adaptations that are required to preserve biogenesis after the structural diversification of mitoribosomes. Furthermore, the structures redefine the ribosome silencing factor (RsfS) family as multifunctional biogenesis factors and identify two new assembly factors (L0R8F8 and mt-ACP) not previously implicated in mitoribosomal biogenesis.

    更新日期:2017-09-15
  • Guide-bound structures of an RNA-targeting A-cleaving CRISPR–Cas13a enzyme
    Nat. Struct. Mol. Biol. (IF 12.595) Pub Date : 2017-09-11
    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. In addition, the orientation of the foreign-derived target-RNA-specifying sequence in the protein interior explains the conformational gating of Cas13a nuclease activation. These results describe how Cas13a enzymes generate functional crRNAs and how catalytic activity is blocked before target-RNA recognition, with implications for both bacterial immunity and diagnostic applications.

    更新日期:2017-09-15
  • Structure of a transcribing RNA polymerase II–DSIF complex reveals a multidentate DNA–RNA clamp
    Nat. Struct. Mol. Biol. (IF 12.595) Pub Date : 
    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. The mobile C-terminal region of DSIF is located near exiting RNA, where it can recruit factors for RNA processing. The structure provides insight into the roles of DSIF during mRNA synthesis.

    更新日期:2017-09-14
Some contents have been Reproduced with permission of the American Chemical Society.
Some contents have been Reproduced by permission of The Royal Society of Chemistry.
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