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  • 1
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    Structure of the eukaryotic MCM complex at 3.8 A (2015)
    Nature Publishing Group (NPG)
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    Publication Date: 2015-07-30
    Description: DNA replication in eukaryotes is strictly regulated by several mechanisms. A central step in this replication is the assembly of the heterohexameric minichromosome maintenance (MCM2-7) helicase complex at replication origins during G1 phase as an inactive double hexamer. Here, using cryo-electron microscopy, we report a near-atomic structure of the MCM2-7 double hexamer purified from yeast G1 chromatin. Our structure shows that two single hexamers, arranged in a tilted and twisted fashion through interdigitated amino-terminal domain interactions, form a kinked central channel. Four constricted rings consisting of conserved interior beta-hairpins from the two single hexamers create a narrow passageway that tightly fits duplex DNA. This narrow passageway, reinforced by the offset of the two single hexamers at the double hexamer interface, is flanked by two pairs of gate-forming subunits, MCM2 and MCM5. These unusual features of the twisted and tilted single hexamers suggest a concerted mechanism for the melting of origin DNA that requires structural deformation of the intervening DNA.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Li, Ningning -- Zhai, Yuanliang -- Zhang, Yixiao -- Li, Wanqiu -- Yang, Maojun -- Lei, Jianlin -- Tye, Bik-Kwoon -- Gao, Ning -- England -- Nature. 2015 Aug 13;524(7564):186-91. doi: 10.1038/nature14685. Epub 2015 Jul 29.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Ministry of Education Key Laboratory of Protein Sciences, Center for Structural Biology, School of Life Sciences, Tsinghua University, Beijing 100084, China. ; 1] Division of Life Science, Hong Kong Universityof Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China [2] Institute for Advanced Study, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China. ; 1] Division of Life Science, Hong Kong Universityof Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China [2] Department of Molecular Biology and Genetics, College of Agriculture and Life Sciences, Cornell University, Ithaca, New York 14853, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26222030" target="_blank"〉PubMed〈/a〉
    Keywords: Binding Sites ; Cell Cycle Proteins/chemistry/metabolism/ultrastructure ; Chromatin/chemistry ; Conserved Sequence ; *Cryoelectron Microscopy ; DNA/chemistry/metabolism/ultrastructure ; DNA-Directed DNA Polymerase/chemistry/ultrastructure ; G1 Phase ; Minichromosome Maintenance Proteins/*chemistry/metabolism/*ultrastructure ; Models, Biological ; Models, Molecular ; Multienzyme Complexes/chemistry/ultrastructure ; Nucleic Acid Denaturation ; Protein Binding ; Protein Multimerization ; Protein Structure, Tertiary ; Protein Subunits/*chemistry/metabolism ; Replication Origin ; Saccharomyces cerevisiae/*chemistry/*ultrastructure ; Saccharomyces cerevisiae Proteins/chemistry/metabolism/ultrastructure
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 2
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    Structural insight into the type-II mitochondrial NADH dehydrogenases (2012)
    Nature Publishing Group (NPG)
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    Publication Date: 2012-10-23
    Description: The single-component type-II NADH dehydrogenases (NDH-2s) serve as alternatives to the multisubunit respiratory complex I (type-I NADH dehydrogenase (NDH-1), also called NADH:ubiquinone oxidoreductase; EC 1.6.5.3) in catalysing electron transfer from NADH to ubiquinone in the mitochondrial respiratory chain. The yeast NDH-2 (Ndi1) oxidizes NADH on the matrix side and reduces ubiquinone to maintain mitochondrial NADH/NAD(+) homeostasis. Ndi1 is a potential therapeutic agent for human diseases caused by complex I defects, particularly Parkinson's disease, because its expression restores the mitochondrial activity in animals with complex I deficiency. NDH-2s in pathogenic microorganisms are viable targets for new antibiotics. Here we solve the crystal structures of Ndi1 in its substrate-free, NADH-, ubiquinone- and NADH-ubiquinone-bound states, to help understand the catalytic mechanism of NDH-2s. We find that Ndi1 homodimerization through its carboxy-terminal domain is critical for its catalytic activity and membrane targeting. The structures reveal two ubiquinone-binding sites (UQ(I) and UQ(II)) in Ndi1. NADH and UQ(I) can bind to Ndi1 simultaneously to form a substrate-protein complex. We propose that UQ(I) interacts with FAD to act as an intermediate for electron transfer, and that NADH transfers electrons through this FAD-UQ(I) complex to UQ(II). Together our data reveal the regulatory and catalytic mechanisms of Ndi1 and may facilitate the development or targeting of NDH-2s for potential therapeutic applications.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Feng, Yue -- Li, Wenfei -- Li, Jian -- Wang, Jiawei -- Ge, Jingpeng -- Xu, Duo -- Liu, Yanjing -- Wu, Kaiqi -- Zeng, Qingyin -- Wu, Jia-Wei -- Tian, Changlin -- Zhou, Bing -- Yang, Maojun -- England -- Nature. 2012 Nov 15;491(7424):478-82. doi: 10.1038/nature11541. Epub 2012 Oct 21.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉State Key Laboratory of Biomembrane and Membrane Biotechnology, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, China.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23086143" target="_blank"〉PubMed〈/a〉
    Keywords: Crystallography, X-Ray ; Electron Transport Complex I/*chemistry/isolation & purification/metabolism ; Mitochondria/*enzymology ; *Models, Molecular ; NAD/chemistry ; Protein Binding ; Protein Multimerization ; Protein Structure, Tertiary ; Saccharomyces cerevisiae/chemistry/enzymology ; Saccharomyces cerevisiae Proteins/*chemistry/isolation & purification/metabolism ; Ubiquinone/chemistry
    Print ISSN: 0028-0836
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 3
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    A long noncoding RNA protects the heart from pathological hypertrophy (2014)
    Nature Publishing Group (NPG)
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    Publication Date: 2014-08-15
    Description: The role of long noncoding RNA (lncRNA) in adult hearts is unknown; also unclear is how lncRNA modulates nucleosome remodelling. An estimated 70% of mouse genes undergo antisense transcription, including myosin heavy chain 7 (Myh7), which encodes molecular motor proteins for heart contraction. Here we identify a cluster of lncRNA transcripts from Myh7 loci and demonstrate a new lncRNA-chromatin mechanism for heart failure. In mice, these transcripts, which we named myosin heavy-chain-associated RNA transcripts (Myheart, or Mhrt), are cardiac-specific and abundant in adult hearts. Pathological stress activates the Brg1-Hdac-Parp chromatin repressor complex to inhibit Mhrt transcription in the heart. Such stress-induced Mhrt repression is essential for cardiomyopathy to develop: restoring Mhrt to the pre-stress level protects the heart from hypertrophy and failure. Mhrt antagonizes the function of Brg1, a chromatin-remodelling factor that is activated by stress to trigger aberrant gene expression and cardiac myopathy. Mhrt prevents Brg1 from recognizing its genomic DNA targets, thus inhibiting chromatin targeting and gene regulation by Brg1. It does so by binding to the helicase domain of Brg1, a domain that is crucial for tethering Brg1 to chromatinized DNA targets. Brg1 helicase has dual nucleic-acid-binding specificities: it is capable of binding lncRNA (Mhrt) and chromatinized--but not naked--DNA. This dual-binding feature of helicase enables a competitive inhibition mechanism by which Mhrt sequesters Brg1 from its genomic DNA targets to prevent chromatin remodelling. A Mhrt-Brg1 feedback circuit is thus crucial for heart function. Human MHRT also originates from MYH7 loci and is repressed in various types of myopathic hearts, suggesting a conserved lncRNA mechanism in human cardiomyopathy. Our studies identify a cardioprotective lncRNA, define a new targeting mechanism for ATP-dependent chromatin-remodelling factors, and establish a new paradigm for lncRNA-chromatin interaction.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4184960/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4184960/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Han, Pei -- Li, Wei -- Lin, Chiou-Hong -- Yang, Jin -- Shang, Ching -- Nurnberg, Sylvia T -- Jin, Kevin Kai -- Xu, Weihong -- Lin, Chieh-Yu -- Lin, Chien-Jung -- Xiong, Yiqin -- Chien, Huan-Chieh -- Zhou, Bin -- Ashley, Euan -- Bernstein, Daniel -- Chen, Peng-Sheng -- Chen, Huei-Sheng Vincent -- Quertermous, Thomas -- Chang, Ching-Pin -- HL105194/HL/NHLBI NIH HHS/ -- HL109512/HL/NHLBI NIH HHS/ -- HL111770/HL/NHLBI NIH HHS/ -- HL116997/HL/NHLBI NIH HHS/ -- HL118087/HL/NHLBI NIH HHS/ -- HL121197/HL/NHLBI NIH HHS/ -- HL71140/HL/NHLBI NIH HHS/ -- HL78931/HL/NHLBI NIH HHS/ -- R01 HL111770/HL/NHLBI NIH HHS/ -- R01 HL116997/HL/NHLBI NIH HHS/ -- R01 HL121197/HL/NHLBI NIH HHS/ -- England -- Nature. 2014 Oct 2;514(7520):102-6. doi: 10.1038/nature13596. Epub 2014 Aug 10.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Krannert Institute of Cardiology and Division of Cardiology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA [2] Division of Cardiovascular Medicine, Cardiovascular Institute, Stanford University School of Medicine, Stanford, California 94305, USA. ; 1] Division of Cardiovascular Medicine, Cardiovascular Institute, Stanford University School of Medicine, Stanford, California 94305, USA [2]. ; Krannert Institute of Cardiology and Division of Cardiology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA. ; Division of Cardiovascular Medicine, Cardiovascular Institute, Stanford University School of Medicine, Stanford, California 94305, USA. ; Stanford Genome Technology Center, Stanford University School of Medicine, Stanford, California 94305, USA. ; Department of Genetics, Pediatrics, and Medicine (Cardiology), Albert Einstein College of Medicine of Yeshiva University, 1301 Morris Park Avenue, Price Center 420, Bronx, New York 10461, USA. ; Department of Pediatrics, Stanford University School of Medicine, Stanford, California 94305, USA. ; Del E. Webb Neuroscience, Aging &Stem Cell Research Center, Sanford/Burnham Medical Research Institute, La Jolla, California 92037, USA. ; 1] Krannert Institute of Cardiology and Division of Cardiology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA [2] Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA [3] Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25119045" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cardiac Myosins/genetics ; Cardiomegaly/*genetics/*pathology/prevention & control ; Cardiomyopathies/genetics/pathology/prevention & control ; Chromatin/genetics/metabolism ; Chromatin Assembly and Disassembly ; DNA Helicases/antagonists & inhibitors/chemistry/genetics/metabolism ; Feedback, Physiological ; Heart Failure/genetics/pathology/prevention & control ; Histone Deacetylases/metabolism ; Humans ; Mice ; Myocardium/metabolism/pathology ; Myosin Heavy Chains/*genetics ; Nuclear Proteins/antagonists & inhibitors/chemistry/genetics/metabolism ; Organ Specificity ; Poly(ADP-ribose) Polymerases/metabolism ; Protein Binding ; Protein Structure, Tertiary ; RNA, Long Noncoding/antagonists & inhibitors/*genetics/metabolism ; Transcription Factors/antagonists & inhibitors/chemistry/genetics/metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 4
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    Structural insight into substrate preference for TET-mediated oxidation (2015)
    Nature Publishing Group (NPG)
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    Publication Date: 2015-11-03
    Description: DNA methylation is an important epigenetic modification. Ten-eleven translocation (TET) proteins are involved in DNA demethylation through iteratively oxidizing 5-methylcytosine (5mC) into 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC). Here we show that human TET1 and TET2 are more active on 5mC-DNA than 5hmC/5fC-DNA substrates. We determine the crystal structures of TET2-5hmC-DNA and TET2-5fC-DNA complexes at 1.80 A and 1.97 A resolution, respectively. The cytosine portion of 5hmC/5fC is specifically recognized by TET2 in a manner similar to that of 5mC in the TET2-5mC-DNA structure, and the pyrimidine base of 5mC/5hmC/5fC adopts an almost identical conformation within the catalytic cavity. However, the hydroxyl group of 5hmC and carbonyl group of 5fC face towards the opposite direction because the hydroxymethyl group of 5hmC and formyl group of 5fC adopt restrained conformations through forming hydrogen bonds with the 1-carboxylate of NOG and N4 exocyclic nitrogen of cytosine, respectively. Biochemical analyses indicate that the substrate preference of TET2 results from the different efficiencies of hydrogen abstraction in TET2-mediated oxidation. The restrained conformation of 5hmC and 5fC within the catalytic cavity may prevent their abstractable hydrogen(s) adopting a favourable orientation for hydrogen abstraction and thus result in low catalytic efficiency. Our studies demonstrate that the substrate preference of TET2 results from the intrinsic value of its substrates at their 5mC derivative groups and suggest that 5hmC is relatively stable and less prone to further oxidation by TET proteins. Therefore, TET proteins are evolutionarily tuned to be less reactive towards 5hmC and facilitate the generation of 5hmC as a potentially stable mark for regulatory functions.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Hu, Lulu -- Lu, Junyan -- Cheng, Jingdong -- Rao, Qinhui -- Li, Ze -- Hou, Haifeng -- Lou, Zhiyong -- Zhang, Lei -- Li, Wei -- Gong, Wei -- Liu, Mengjie -- Sun, Chang -- Yin, Xiaotong -- Li, Jie -- Tan, Xiangshi -- Wang, Pengcheng -- Wang, Yinsheng -- Fang, Dong -- Cui, Qiang -- Yang, Pengyuan -- He, Chuan -- Jiang, Hualiang -- Luo, Cheng -- Xu, Yanhui -- Howard Hughes Medical Institute/ -- England -- Nature. 2015 Nov 5;527(7576):118-22. doi: 10.1038/nature15713. Epub 2015 Oct 28.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Fudan University Shanghai Cancer Center, Institute of Biomedical Sciences, Shanghai Medical College of Fudan University, Shanghai 200032, China. ; Key Laboratory of Molecular Medicine, Ministry of Education, Department of Systems Biology for Medicine, School of Basic Medical Sciences, Shanghai Medical College of Fudan University, Shanghai 200032, China. ; State Key Laboratory of Genetic Engineering, Collaborative Innovation Center of Genetics and Development, School of Life Sciences, Fudan University, Shanghai 200433, China. ; Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China. ; Beijing Synchrotron Radiation Facility, Institute of High Energy Physics, Chinese Academy of Sciences, Beijing 100049, China. ; Laboratory of Structural Biology, Tsinghua University, Beijing 100084, China. ; MOE Laboratory of Protein Science, School of Medicine, Tsinghua University, Beijing 100084, China. ; Department of Chemistry, University of California-Riverside, Riverside, California 92521-0403, USA. ; Theoretical Chemistry Institute, Department of Chemistry, University of Wisconsin-Madison, 1101 University Avenue, Madison, Wisconsin 53706, USA. ; Department of Chemistry and Institute for Biophysical Dynamics, The University of Chicago, 929 East 57th Street, Chicago, Illinois 60637, USA. ; Howard Hughes Medical Institute, The University of Chicago, 929 East 57th Street, Chicago, Illinois 60637, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26524525" target="_blank"〉PubMed〈/a〉
    Keywords: 5-Methylcytosine/metabolism ; Biocatalysis ; Catalytic Domain ; Crystallography, X-Ray ; Cytosine/analogs & derivatives/metabolism ; DNA/*chemistry/*metabolism ; DNA Methylation ; DNA-Binding Proteins/*chemistry/*metabolism ; Humans ; Hydrogen Bonding ; Models, Molecular ; Oxidation-Reduction ; Protein Binding ; Proto-Oncogene Proteins/*chemistry/*metabolism ; Substrate Specificity
    Print ISSN: 0028-0836
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 5
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    ZMYND11 links histone H3.3K36me3 to transcription elongation and tumour suppression (2014)
    Nature Publishing Group (NPG)
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    Publication Date: 2014-03-05
    Description: Recognition of modified histones by 'reader' proteins plays a critical role in the regulation of chromatin. H3K36 trimethylation (H3K36me3) is deposited onto the nucleosomes in the transcribed regions after RNA polymerase II elongation. In yeast, this mark in turn recruits epigenetic regulators to reset the chromatin to a relatively repressive state, thus suppressing cryptic transcription. However, much less is known about the role of H3K36me3 in transcription regulation in mammals. This is further complicated by the transcription-coupled incorporation of the histone variant H3.3 in gene bodies. Here we show that the candidate tumour suppressor ZMYND11 specifically recognizes H3K36me3 on H3.3 (H3.3K36me3) and regulates RNA polymerase II elongation. Structural studies show that in addition to the trimethyl-lysine binding by an aromatic cage within the PWWP domain, the H3.3-dependent recognition is mediated by the encapsulation of the H3.3-specific 'Ser 31' residue in a composite pocket formed by the tandem bromo-PWWP domains of ZMYND11. Chromatin immunoprecipitation followed by sequencing shows a genome-wide co-localization of ZMYND11 with H3K36me3 and H3.3 in gene bodies, and its occupancy requires the pre-deposition of H3.3K36me3. Although ZMYND11 is associated with highly expressed genes, it functions as an unconventional transcription co-repressor by modulating RNA polymerase II at the elongation stage. ZMYND11 is critical for the repression of a transcriptional program that is essential for tumour cell growth; low expression levels of ZMYND11 in breast cancer patients correlate with worse prognosis. Consistently, overexpression of ZMYND11 suppresses cancer cell growth in vitro and tumour formation in mice. Together, this study identifies ZMYND11 as an H3.3-specific reader of H3K36me3 that links the histone-variant-mediated transcription elongation control to tumour suppression.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4142212/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4142212/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Wen, Hong -- Li, Yuanyuan -- Xi, Yuanxin -- Jiang, Shiming -- Stratton, Sabrina -- Peng, Danni -- Tanaka, Kaori -- Ren, Yongfeng -- Xia, Zheng -- Wu, Jun -- Li, Bing -- Barton, Michelle C -- Li, Wei -- Li, Haitao -- Shi, Xiaobing -- CA016672/CA/NCI NIH HHS/ -- P30 CA016672/CA/NCI NIH HHS/ -- R01 GM090077/GM/NIGMS NIH HHS/ -- R01 HG007538/HG/NHGRI NIH HHS/ -- R01GM090077/GM/NIGMS NIH HHS/ -- R01HG007538/HG/NHGRI NIH HHS/ -- England -- Nature. 2014 Apr 10;508(7495):263-8. doi: 10.1038/nature13045. Epub 2014 Mar 2.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Department of Biochemistry and Molecular Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA [2] Center for Cancer Epigenetics, Center for Genetics and Genomics, and Center for Stem Cell and Developmental Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA [3]. ; 1] MOE Key Laboratory of Protein Sciences, Center for Structural Biology, School of Life Sciences, Tsinghua University, Beijing 100084, China [2] Department of Basic Medical Sciences, School of Medicine, Tsinghua University, Beijing 100084, China [3]. ; 1] Dan L. Duncan Cancer Center, Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA [2]. ; Department of Biochemistry and Molecular Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA. ; 1] MOE Key Laboratory of Protein Sciences, Center for Structural Biology, School of Life Sciences, Tsinghua University, Beijing 100084, China [2] Department of Basic Medical Sciences, School of Medicine, Tsinghua University, Beijing 100084, China. ; Dan L. Duncan Cancer Center, Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA. ; Department of Molecular Biology, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA. ; 1] Department of Biochemistry and Molecular Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA [2] Center for Cancer Epigenetics, Center for Genetics and Genomics, and Center for Stem Cell and Developmental Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA [3] Genes and Development Graduate Program, The University of Texas Graduate School of Biomedical Sciences, Houston, Teaxs 77030, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24590075" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Animals ; Breast Neoplasms/*genetics/metabolism/*pathology ; Carrier Proteins/chemistry/*metabolism ; Chromatin/genetics/metabolism ; Co-Repressor Proteins/chemistry/metabolism ; Crystallography, X-Ray ; Disease-Free Survival ; Female ; Gene Expression Regulation, Neoplastic/genetics ; Histones/chemistry/*metabolism ; Humans ; Lysine/*metabolism ; Methylation ; Mice ; Mice, Nude ; Models, Molecular ; Molecular Sequence Data ; Oncogenes/genetics ; Prognosis ; Protein Binding ; Protein Conformation ; Protein Structure, Tertiary ; RNA Polymerase II/*metabolism ; Substrate Specificity ; *Transcription Elongation, Genetic
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  • 6
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    Required enhancer-matrin-3 network interactions for a homeodomain transcription program (2014)
    Nature Publishing Group (NPG)
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    Publication Date: 2014-08-15
    Description: Homeodomain proteins, described 30 years ago, exert essential roles in development as regulators of target gene expression; however, the molecular mechanisms underlying transcriptional activity of homeodomain factors remain poorly understood. Here investigation of a developmentally required POU-homeodomain transcription factor, Pit1 (also known as Pou1f1), has revealed that, unexpectedly, binding of Pit1-occupied enhancers to a nuclear matrin-3-rich network/architecture is a key event in effective activation of the Pit1-regulated enhancer/coding gene transcriptional program. Pit1 association with Satb1 (ref. 8) and beta-catenin is required for this tethering event. A naturally occurring, dominant negative, point mutation in human PIT1(R271W), causing combined pituitary hormone deficiency, results in loss of Pit1 association with beta-catenin and Satb1 and therefore the matrin-3-rich network, blocking Pit1-dependent enhancer/coding target gene activation. This defective activation can be rescued by artificial tethering of the mutant R271W Pit1 protein to the matrin-3 network, bypassing the pre-requisite association with beta-catenin and Satb1 otherwise required. The matrin-3 network-tethered R271W Pit1 mutant, but not the untethered protein, restores Pit1-dependent activation of the enhancers and recruitment of co-activators, exemplified by p300, causing both enhancer RNA transcription and target gene activation. These studies have thus revealed an unanticipated homeodomain factor/beta-catenin/Satb1-dependent localization of target gene regulatory enhancer regions to a subnuclear architectural structure that serves as an underlying mechanism by which an enhancer-bound homeodomain factor effectively activates developmental gene transcriptional programs.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4358797/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4358797/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Skowronska-Krawczyk, Dorota -- Ma, Qi -- Schwartz, Michal -- Scully, Kathleen -- Li, Wenbo -- Liu, Zhijie -- Taylor, Havilah -- Tollkuhn, Jessica -- Ohgi, Kenneth A -- Notani, Dimple -- Kohwi, Yoshinori -- Kohwi-Shigematsu, Terumi -- Rosenfeld, Michael G -- CA173903/CA/NCI NIH HHS/ -- DK018477/DK/NIDDK NIH HHS/ -- DK039949/DK/NIDDK NIH HHS/ -- HL065445/HL/NHLBI NIH HHS/ -- NS034934/NS/NINDS NIH HHS/ -- P01 DK074868/DK/NIDDK NIH HHS/ -- P30 NS047101/NS/NINDS NIH HHS/ -- R01 CA173903/CA/NCI NIH HHS/ -- R01 DK018477/DK/NIDDK NIH HHS/ -- R01 HL065445/HL/NHLBI NIH HHS/ -- R01 NS034934/NS/NINDS NIH HHS/ -- R01 NS048243/NS/NINDS NIH HHS/ -- R37 CA039681/CA/NCI NIH HHS/ -- R37 DK039949/DK/NIDDK NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2014 Oct 9;514(7521):257-61. doi: 10.1038/nature13573. Epub 2014 Aug 3.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Howard Hughes Medical Institute, Department of Medicine, School of Medicine, University of California, San Diego, La Jolla, California 92093, USA. ; 1] Howard Hughes Medical Institute, Department of Medicine, School of Medicine, University of California, San Diego, La Jolla, California 92093, USA [2] The Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan, 5290002, Israel. ; Lawrence Berkeley National Laboratory, Berkeley, California 94720, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25119036" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cells, Cultured ; Enhancer Elements, Genetic/*genetics ; *Gene Expression Regulation, Developmental ; Homeodomain Proteins/genetics/*metabolism ; Humans ; Matrix Attachment Region Binding Proteins/metabolism ; Mice ; Nuclear Matrix-Associated Proteins/*metabolism ; Pituitary Gland/embryology/metabolism ; Protein Binding ; RNA-Binding Proteins/*metabolism ; Transcription Factor Pit-1/genetics/metabolism ; *Transcription, Genetic/genetics ; beta Catenin/metabolism
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  • 7
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    A G protein-coupled receptor is a plasma membrane receptor for the plant hormone abscisic acid (2007)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2007-03-10
    Description: The plant hormone abscisic acid (ABA) regulates many physiological and developmental processes in plants. The mechanism of ABA perception at the cell surface is not understood. Here, we report that a G protein-coupled receptor genetically and physically interacts with the G protein alpha subunit GPA1 to mediate all known ABA responses in Arabidopsis. Overexpressing this receptor results in an ABA-hypersensitive phenotype. This receptor binds ABA with high affinity at physiological concentration with expected kinetics and stereospecificity. The binding of ABA to the receptor leads to the dissociation of the receptor-GPA1 complex in yeast. Our results demonstrate that this G protein-coupled receptor is a plasma membrane ABA receptor.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Liu, Xigang -- Yue, Yanling -- Li, Bin -- Nie, Yanli -- Li, Wei -- Wu, Wei-Hua -- Ma, Ligeng -- New York, N.Y. -- Science. 2007 Mar 23;315(5819):1712-6. Epub 2007 Mar 8.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉National Institute of Biological Sciences, 7 Science Park Road, Zhongguancun Life Science Park, Beijing 102206, China.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/17347412" target="_blank"〉PubMed〈/a〉
    Keywords: Abscisic Acid/*metabolism/pharmacology ; Arabidopsis/genetics/*metabolism ; Arabidopsis Proteins/chemistry/genetics/*metabolism ; GTP-Binding Protein alpha Subunits/metabolism ; Gene Expression Profiling ; Genes, Reporter ; Germination ; Models, Biological ; Mutation ; Plant Growth Regulators/*metabolism ; Plant Leaves/cytology/physiology ; Plants, Genetically Modified ; Potassium Channels/metabolism ; Protein Binding ; Receptors, G-Protein-Coupled/chemistry/genetics/*metabolism ; Recombinant Proteins/metabolism ; Seeds/growth & development ; *Signal Transduction
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
    Published by American Association for the Advancement of Science (AAAS)
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  • 8
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    Probing transcription factor dynamics at the single-molecule level in a living cell (2007)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2007-05-26
    Description: Transcription factors regulate gene expression through their binding to DNA. In a living Escherichia coli cell, we directly observed specific binding of a lac repressor, labeled with a fluorescent protein, to a chromosomal lac operator. Using single-molecule detection techniques, we measured the kinetics of binding and dissociation of the repressor in response to metabolic signals. Furthermore, we characterized the nonspecific binding to DNA, one-dimensional (1D) diffusion along DNA segments, and 3D translocation among segments through cytoplasm at the single-molecule level. In searching for the operator, a lac repressor spends approximately 90% of time nonspecifically bound to and diffusing along DNA with a residence time of 〈5 milliseconds. The methods and findings can be generalized to other nucleic acid binding proteins.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2853898/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2853898/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Elf, Johan -- Li, Gene-Wei -- Xie, X Sunney -- DP1 OD000277/OD/NIH HHS/ -- DP1 OD000277-02/OD/NIH HHS/ -- New York, N.Y. -- Science. 2007 May 25;316(5828):1191-4.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/17525339" target="_blank"〉PubMed〈/a〉
    Keywords: Bacterial Proteins/genetics/*metabolism ; DNA, Bacterial/*metabolism ; Diffusion ; Escherichia coli/*genetics ; Escherichia coli Proteins/*metabolism ; Kinetics ; *Lac Operon ; Lac Repressors ; Luminescent Proteins/genetics/metabolism ; Microscopy, Fluorescence ; Operator Regions, Genetic ; Protein Binding ; Repressor Proteins/*metabolism ; Signal Transduction
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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    SMN and symmetric arginine dimethylation of RNA polymerase II C-terminal domain control termination (2015)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2015-12-25
    Description: The carboxy-terminal domain (CTD) of the RNA polymerase II (RNAP II) subunit POLR2A is a platform for modifications specifying the recruitment of factors that regulate transcription, mRNA processing, and chromatin remodelling. Here we show that a CTD arginine residue (R1810 in human) that is conserved across vertebrates is symmetrically dimethylated (me2s). This R1810me2s modification requires protein arginine methyltransferase 5 (PRMT5) and recruits the Tudor domain of the survival of motor neuron (SMN, also known as GEMIN1) protein, which is mutated in spinal muscular atrophy. SMN interacts with senataxin, which is sometimes mutated in ataxia oculomotor apraxia type 2 and amyotrophic lateral sclerosis. Because POLR2A R1810me2s and SMN, like senataxin, are required for resolving RNA-DNA hybrids created by RNA polymerase II that form R-loops in transcription termination regions, we propose that R1810me2s, SMN, and senataxin are components of an R-loop resolution pathway. Defects in this pathway can influence transcription termination and may contribute to neurodegenerative disorders.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zhao, Dorothy Yanling -- Gish, Gerald -- Braunschweig, Ulrich -- Li, Yue -- Ni, Zuyao -- Schmitges, Frank W -- Zhong, Guoqing -- Liu, Ke -- Li, Weiguo -- Moffat, Jason -- Vedadi, Masoud -- Min, Jinrong -- Pawson, Tony J -- Blencowe, Benjamin J -- Greenblatt, Jack F -- Canadian Institutes of Health Research/Canada -- England -- Nature. 2016 Jan 7;529(7584):48-53. doi: 10.1038/nature16469. Epub 2015 Dec 23.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Donnelly Centre, University of Toronto, Toronto, Ontario M5S 3E1, Canada. ; Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, 600 University Avenue, Toronto, Ontario M5G 1X5, Canada. ; Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5S 1A8, Canada. ; Department of Computer Science, University of Toronto, Toronto, Ontario M5S 3G4, Canada. ; Structural Genomics Consortium, University of Toronto, Toronto, Ontario M5G 1L7, Canada.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26700805" target="_blank"〉PubMed〈/a〉
    Keywords: Arginine/*metabolism ; Cell Line ; DNA Damage ; Humans ; Methylation ; Neurodegenerative Diseases/genetics ; Protein Binding ; Protein Structure, Tertiary ; Protein-Arginine N-Methyltransferases/genetics/metabolism ; RNA Helicases/genetics/metabolism ; RNA Polymerase II/*chemistry/*metabolism ; Survival of Motor Neuron 1 Protein/genetics/*metabolism ; Transcription Elongation, Genetic ; *Transcription Termination, Genetic
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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    Structure of the SecY channel during initiation of protein translocation (2013)
    Nature Publishing Group (NPG)
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    Publication Date: 2013-10-25
    Description: Many secretory proteins are targeted by signal sequences to a protein-conducting channel, formed by prokaryotic SecY or eukaryotic Sec61 complexes, and are translocated across the membrane during their synthesis. Crystal structures of the inactive channel show that the SecY subunit of the heterotrimeric complex consists of two halves that form an hourglass-shaped pore with a constriction in the middle of the membrane and a lateral gate that faces the lipid phase. The closed channel has an empty cytoplasmic funnel and an extracellular funnel that is filled with a small helical domain, called the plug. During initiation of translocation, a ribosome-nascent chain complex binds to the SecY (or Sec61) complex, resulting in insertion of the nascent chain. However, the mechanism of channel opening during translocation is unclear. Here we have addressed this question by determining structures of inactive and active ribosome-channel complexes with cryo-electron microscopy. Non-translating ribosome-SecY channel complexes derived from Methanocaldococcus jannaschii or Escherichia coli show the channel in its closed state, and indicate that ribosome binding per se causes only minor changes. The structure of an active E. coli ribosome-channel complex demonstrates that the nascent chain opens the channel, causing mostly rigid body movements of the amino- and carboxy-terminal halves of SecY. In this early translocation intermediate, the polypeptide inserts as a loop into the SecY channel with the hydrophobic signal sequence intercalated into the open lateral gate. The nascent chain also forms a loop on the cytoplasmic surface of SecY rather than entering the channel directly.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3948209/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3948209/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Park, Eunyong -- Menetret, Jean-Francois -- Gumbart, James C -- Ludtke, Steven J -- Li, Weikai -- Whynot, Andrew -- Rapoport, Tom A -- Akey, Christopher W -- GM052586/GM/NIGMS NIH HHS/ -- GM067887/GM/NIGMS NIH HHS/ -- GM080139/GM/NIGMS NIH HHS/ -- GM45377/GM/NIGMS NIH HHS/ -- K99 HL097083/HL/NHLBI NIH HHS/ -- R00 HL097083/HL/NHLBI NIH HHS/ -- R01 GM045377/GM/NIGMS NIH HHS/ -- R01 GM052586/GM/NIGMS NIH HHS/ -- R01 GM067887/GM/NIGMS NIH HHS/ -- R01 GM080139/GM/NIGMS NIH HHS/ -- R01 HL121718/HL/NHLBI NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2014 Feb 6;506(7486):102-6. doi: 10.1038/nature12720. Epub 2013 Oct 23.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Cell Biology and Howard Hughes Medical Institute, Harvard Medical School, 240 Longwood Avenue, Boston, Massachusetts 02115, USA. ; Department of Physiology and Biophysics, Boston University School of Medicine, 700 Albany Street, Boston, Massachusetts 02118-2526, USA. ; School of Physics, Georgia Institute of Technology, Atlanta, Georgia 30332, USA. ; National Center for Macromolecular Imaging, Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, 1 Baylor Plaza, Houston, Texas 77030, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24153188" target="_blank"〉PubMed〈/a〉
    Keywords: Cryoelectron Microscopy ; Escherichia coli/*chemistry/ultrastructure ; Escherichia coli Proteins/chemistry/isolation & ; purification/*metabolism/*ultrastructure ; Methanocaldococcus/*chemistry/ultrastructure ; Models, Molecular ; Multiprotein Complexes/chemistry/isolation & ; purification/metabolism/ultrastructure ; Peptides/chemistry/metabolism ; Protein Binding ; *Protein Biosynthesis ; Protein Subunits/chemistry/isolation & purification/metabolism ; Protein Transport ; Ribosomes/chemistry/*metabolism/*ultrasonography
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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