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  • 1
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    Structures and reaction mechanisms of the two related enzymes, PurN and PurU (2013)
    Oxford University Press
    Details
    Publication Date: 2013-12-03
    Description: The crystal structures of glycinamide ribonucleotide transformylases (PurNs) from Aquifex aeolicus ( Aa ), Geobacillus kaustophilus ( Gk ) and Symbiobacterium toebii ( St ), and of formyltetrahydrofolate hydrolase (PurU) from Thermus thermophilus ( Tt ) were determined. The monomer structures of the determined PurN and PurU were very similar to the known structure of PurN, but oligomeric states were different; Aa PurN and St PurN formed dimers, Gk PurN formed monomer and PurU formed tetramer in the crystals. PurU had a regulatory ACT domain in its N-terminal side. So far several structures of PurUs have been determined, yet, the mechanisms of the catalysis and the regulation of PurU have not been elucidated. We, therefore, modelled ligand-bound structures of PurN and PurU, and performed molecular dynamics simulations to elucidate the reaction mechanisms. The evolutionary relationship of the two enzymes is discussed based on the comparisons of the structures and the catalytic mechanisms.
    Print ISSN: 0021-924X
    Electronic ISSN: 1756-2651
    Topics: Biology , Chemistry and Pharmacology
    Published by Oxford University Press on behalf of The Japanese Biochemical Society (JBS).
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  • 2
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    Tertiary structure of bacterial selenocysteine tRNA (2013)
    Oxford University Press
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    Publication Date: 2013-07-16
    Description: Selenocysteine (Sec) is translationally incorporated into proteins in response to the UGA codon. The tRNA specific to Sec (tRNA Sec ) is first ligated with serine by seryl-tRNA synthetase (SerRS). In the present study, we determined the 3.1 Å crystal structure of the tRNA Sec from the bacterium Aquifex aeolicus , in complex with the heterologous SerRS from the archaeon Methanopyrus kandleri . The bacterial tRNA Sec assumes the L-shaped structure, from which the long extra arm protrudes. Although the D-arm conformation and the extra-arm orientation are similar to those of eukaryal/archaeal tRNA Sec s, A. aeolicus tRNA Sec has unique base triples, G14:C21:U8 and C15:G20a:G48, which occupy the positions corresponding to the U8:A14 and R15:Y48 tertiary base pairs of canonical tRNAs. Methanopyrus kandleri SerRS exhibited serine ligation activity toward A. aeolicus tRNA Sec in vitro . The SerRS N-terminal domain interacts with the extra-arm stem and the outer corner of tRNA Sec . Similar interactions exist in the reported tRNA Ser and SerRS complex structure from the bacterium Thermus thermophilus . Although the catalytic C-terminal domain of M. kandleri SerRS lacks interactions with A. aeolicus tRNA Sec in the present complex structure, the conformational flexibility of SerRS is likely to allow the CCA terminal region of tRNA Sec to enter the SerRS catalytic site.
    Print ISSN: 0305-1048
    Electronic ISSN: 1362-4962
    Topics: Biology
    Published by Oxford University Press
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  • 3
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    Molecular mechanism of phenylimidazole-type GSM [Biochemistry] (2014)
    National Academy of Sciences
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    Publication Date: 2014-07-23
    Description: γ-Secretase is an intramembrane-cleaving protease responsible for the generation of amyloid-β (Aβ) peptides. Recently, a series of compounds called γ-secretase modulators (GSMs) has been shown to decrease the levels of long toxic Aβ species (i.e., Aβ42), with a concomitant elevation of the production of shorter Aβ species. In this study,...
    Print ISSN: 0027-8424
    Electronic ISSN: 1091-6490
    Topics: Biology , Medicine , Natural Sciences in General
    Published by National Academy of Sciences
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  • 4
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    Two enzymes bound to one transfer RNA assume alternative conformations for consecutive reactions (2010)
    Nature Publishing Group (NPG)
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    Publication Date: 2010-10-01
    Description: In most bacteria and all archaea, glutamyl-tRNA synthetase (GluRS) glutamylates both tRNA(Glu) and tRNA(Gln), and then Glu-tRNA(Gln) is selectively converted to Gln-tRNA(Gln) by a tRNA-dependent amidotransferase. The mechanisms by which the two enzymes recognize their substrate tRNA(s), and how they cooperate with each other in Gln-tRNA(Gln) synthesis, remain to be determined. Here we report the formation of the 'glutamine transamidosome' from the bacterium Thermotoga maritima, consisting of tRNA(Gln), GluRS and the heterotrimeric amidotransferase GatCAB, and its crystal structure at 3.35 A resolution. The anticodon-binding body of GluRS recognizes the common features of tRNA(Gln) and tRNA(Glu), whereas the tail body of GatCAB recognizes the outer corner of the L-shaped tRNA(Gln) in a tRNA(Gln)-specific manner. GluRS is in the productive form, as its catalytic body binds to the amino-acid-acceptor arm of tRNA(Gln). In contrast, GatCAB is in the non-productive form: the catalytic body of GatCAB contacts that of GluRS and is located near the acceptor stem of tRNA(Gln), in an appropriate site to wait for the completion of Glu-tRNA(Gln) formation by GluRS. We identified the hinges between the catalytic and anticodon-binding bodies of GluRS and between the catalytic and tail bodies of GatCAB, which allow both GluRS and GatCAB to adopt the productive and non-productive forms. The catalytic bodies of the two enzymes compete for the acceptor arm of tRNA(Gln) and therefore cannot assume their productive forms simultaneously. The transition from the present glutamylation state, with the productive GluRS and the non-productive GatCAB, to the putative amidation state, with the non-productive GluRS and the productive GatCAB, requires an intermediate state with the two enzymes in their non-productive forms, for steric reasons. The proposed mechanism explains how the transamidosome efficiently performs the two consecutive steps of Gln-tRNA(Gln) formation, with a low risk of releasing the unstable intermediate Glu-tRNA(Gln).〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ito, Takuhiro -- Yokoyama, Shigeyuki -- England -- Nature. 2010 Sep 30;467(7315):612-6. doi: 10.1038/nature09411.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biophysics and Biochemistry, Graduate School of Science, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20882017" target="_blank"〉PubMed〈/a〉
    Keywords: Anticodon/genetics ; Biocatalysis ; Crystallography, X-Ray ; Electrophoretic Mobility Shift Assay ; Glutamate-tRNA Ligase/*chemistry/*metabolism ; Models, Molecular ; Molecular Conformation ; Nitrogenous Group Transferases/*chemistry/*metabolism ; Protein Binding ; RNA, Transfer, Gln/biosynthesis/*chemistry/*metabolism ; RNA, Transfer, Glu/chemistry/metabolism ; Staphylococcus aureus/enzymology ; Substrate Specificity ; Thermotoga maritima/*enzymology
    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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  • 5
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    Crystal structure of bacterial RNA polymerase bound with a transcription inhibitor protein (2010)
    Nature Publishing Group (NPG)
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    Publication Date: 2010-12-03
    Description: The multi-subunit DNA-dependent RNA polymerase (RNAP) is the principal enzyme of transcription for gene expression. Transcription is regulated by various transcription factors. Gre factor homologue 1 (Gfh1), found in the Thermus genus, is a close homologue of the well-conserved bacterial transcription factor GreA, and inhibits transcription initiation and elongation by binding directly to RNAP. The structural basis of transcription inhibition by Gfh1 has remained elusive, although the crystal structures of RNAP and Gfh1 have been determined separately. Here we report the crystal structure of Thermus thermophilus RNAP complexed with Gfh1. The amino-terminal coiled-coil domain of Gfh1 fully occludes the channel formed between the two central modules of RNAP; this channel would normally be used for nucleotide triphosphate (NTP) entry into the catalytic site. Furthermore, the tip of the coiled-coil domain occupies the NTP beta-gamma phosphate-binding site. The NTP-entry channel is expanded, because the central modules are 'ratcheted' relative to each other by approximately 7 degrees , as compared with the previously reported elongation complexes. This 'ratcheted state' is an alternative structural state, defined by a newly acquired contact between the central modules. Therefore, the shape of Gfh1 is appropriate to maintain RNAP in the ratcheted state. Simultaneously, the ratcheting expands the nucleic-acid-binding channel, and kinks the bridge helix, which connects the central modules. Taken together, the present results reveal that Gfh1 inhibits transcription by preventing NTP binding and freezing RNAP in the alternative structural state. The ratcheted state might also be associated with other aspects of transcription, such as RNAP translocation and transcription termination.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Tagami, Shunsuke -- Sekine, Shun-Ichi -- Kumarevel, Thirumananseri -- Hino, Nobumasa -- Murayama, Yuko -- Kamegamori, Syunsuke -- Yamamoto, Masaki -- Sakamoto, Kensaku -- Yokoyama, Shigeyuki -- England -- Nature. 2010 Dec 16;468(7326):978-82. doi: 10.1038/nature09573. Epub 2010 Dec 1.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biophysics and Biochemistry, Graduate School of Science, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21124318" target="_blank"〉PubMed〈/a〉
    Keywords: Bacterial Proteins/*chemistry/*metabolism ; Crystallography, X-Ray ; DNA/chemistry/metabolism ; DNA-Directed RNA Polymerases/*chemistry/*metabolism ; Models, Molecular ; Protein Conformation ; Thermus thermophilus/chemistry/*enzymology ; *Transcription, 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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  • 6
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    Decameric SelA*tRNA(Sec) ring structure reveals mechanism of bacterial selenocysteine formation (2013)
    American Association for the Advancement of Science (AAAS)
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    Publication Date: 2013-04-06
    Description: The 21st amino acid, selenocysteine (Sec), is synthesized on its cognate transfer RNA (tRNA(Sec)). In bacteria, SelA synthesizes Sec from Ser-tRNA(Sec), whereas in archaea and eukaryotes SepSecS forms Sec from phosphoserine (Sep) acylated to tRNA(Sec). We determined the crystal structures of Aquifex aeolicus SelA complexes, which revealed a ring-shaped homodecamer that binds 10 tRNA(Sec) molecules, each interacting with four SelA subunits. The SelA N-terminal domain binds the tRNA(Sec)-specific D-arm structure, thereby discriminating Ser-tRNA(Sec) from Ser-tRNA(Ser). A large cleft is created between two subunits and accommodates the 3'-terminal region of Ser-tRNA(Sec). The SelA structures together with in vivo and in vitro enzyme assays show decamerization to be essential for SelA function. SelA catalyzes pyridoxal 5'-phosphate-dependent Sec formation involving Arg residues nonhomologous to those in SepSecS. Different protein architecture and substrate coordination of the bacterial enzyme provide structural evidence for independent evolution of the two Sec synthesis systems present in nature.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3976565/" 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/PMC3976565/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Itoh, Yuzuru -- Brocker, Markus J -- Sekine, Shun-ichi -- Hammond, Gifty -- Suetsugu, Shiro -- Soll, Dieter -- Yokoyama, Shigeyuki -- GM22854/GM/NIGMS NIH HHS/ -- R01 GM022854/GM/NIGMS NIH HHS/ -- New York, N.Y. -- Science. 2013 Apr 5;340(6128):75-8. doi: 10.1126/science.1229521.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉RIKEN Systems and Structural Biology Center, Tsurumi, Yokohama 230-0045, Japan.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23559248" target="_blank"〉PubMed〈/a〉
    Keywords: Arginine/chemistry ; Bacteria/*enzymology ; Bacterial Proteins/*chemistry ; Catalysis ; Catalytic Domain ; Crystallography, X-Ray ; Protein Multimerization ; Protein Structure, Secondary ; Protein Structure, Tertiary ; Pyridoxal Phosphate/chemistry ; RNA, Transfer, Amino Acyl/*chemistry ; Selenocysteine/*biosynthesis ; Transferases/*chemistry
    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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  • 7
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    Rotation mechanism of Enterococcus hirae V1-ATPase based on asymmetric crystal structures (2013)
    Nature Publishing Group (NPG)
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    Publication Date: 2013-01-22
    Description: In various cellular membrane systems, vacuolar ATPases (V-ATPases) function as proton pumps, which are involved in many processes such as bone resorption and cancer metastasis, and these membrane proteins represent attractive drug targets for osteoporosis and cancer. The hydrophilic V(1) portion is known as a rotary motor, in which a central axis DF complex rotates inside a hexagonally arranged catalytic A(3)B(3) complex using ATP hydrolysis energy, but the molecular mechanism is not well defined owing to a lack of high-resolution structural information. We previously reported on the in vitro expression, purification and reconstitution of Enterococcus hirae V(1)-ATPase from the A(3)B(3) and DF complexes. Here we report the asymmetric structures of the nucleotide-free (2.8 A) and nucleotide-bound (3.4 A) A(3)B(3) complex that demonstrate conformational changes induced by nucleotide binding, suggesting a binding order in the right-handed rotational orientation in a cooperative manner. The crystal structures of the nucleotide-free (2.2 A) and nucleotide-bound (2.7 A) V(1)-ATPase are also reported. The more tightly packed nucleotide-binding site seems to be induced by DF binding, and ATP hydrolysis seems to be stimulated by the approach of a conserved arginine residue. To our knowledge, these asymmetric structures represent the first high-resolution view of the rotational mechanism of V(1)-ATPase.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Arai, Satoshi -- Saijo, Shinya -- Suzuki, Kano -- Mizutani, Kenji -- Kakinuma, Yoshimi -- Ishizuka-Katsura, Yoshiko -- Ohsawa, Noboru -- Terada, Takaho -- Shirouzu, Mikako -- Yokoyama, Shigeyuki -- Iwata, So -- Yamato, Ichiro -- Murata, Takeshi -- England -- Nature. 2013 Jan 31;493(7434):703-7. doi: 10.1038/nature11778. Epub 2013 Jan 13.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Chemistry, Graduate School of Science, Chiba University, 1-33 Yayoi-cho, Inage, Chiba 263-8522, Japan.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23334411" target="_blank"〉PubMed〈/a〉
    Keywords: Binding Sites ; Crystallization ; Enterococcus/*enzymology/genetics ; *Models, Molecular ; Mutation ; Nucleotides/metabolism ; Protein Binding ; Protein Structure, Tertiary ; Protein Subunits ; Rotation ; Vacuolar Proton-Translocating ATPases/*chemistry/genetics
    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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  • 8
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    A small-molecule AdipoR agonist for type 2 diabetes and short life in obesity (2013)
    Nature Publishing Group (NPG)
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    Publication Date: 2013-11-01
    Description: Adiponectin secreted from adipocytes binds to adiponectin receptors AdipoR1 and AdipoR2, and exerts antidiabetic effects via activation of AMPK and PPAR-alpha pathways, respectively. Levels of adiponectin in plasma are reduced in obesity, which causes insulin resistance and type 2 diabetes. Thus, orally active small molecules that bind to and activate AdipoR1 and AdipoR2 could ameliorate obesity-related diseases such as type 2 diabetes. Here we report the identification of orally active synthetic small-molecule AdipoR agonists. One of these compounds, AdipoR agonist (AdipoRon), bound to both AdipoR1 and AdipoR2 in vitro. AdipoRon showed very similar effects to adiponectin in muscle and liver, such as activation of AMPK and PPAR-alpha pathways, and ameliorated insulin resistance and glucose intolerance in mice fed a high-fat diet, which was completely obliterated in AdipoR1 and AdipoR2 double-knockout mice. Moreover, AdipoRon ameliorated diabetes of genetically obese rodent model db/db mice, and prolonged the shortened lifespan of db/db mice on a high-fat diet. Thus, orally active AdipoR agonists such as AdipoRon are a promising therapeutic approach for the treatment of obesity-related diseases such as type 2 diabetes.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Okada-Iwabu, Miki -- Yamauchi, Toshimasa -- Iwabu, Masato -- Honma, Teruki -- Hamagami, Ken-ichi -- Matsuda, Koichi -- Yamaguchi, Mamiko -- Tanabe, Hiroaki -- Kimura-Someya, Tomomi -- Shirouzu, Mikako -- Ogata, Hitomi -- Tokuyama, Kumpei -- Ueki, Kohjiro -- Nagano, Tetsuo -- Tanaka, Akiko -- Yokoyama, Shigeyuki -- Kadowaki, Takashi -- England -- Nature. 2013 Nov 28;503(7477):493-9. doi: 10.1038/nature12656. Epub 2013 Oct 30.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan [2] Department of Integrated Molecular Science on Metabolic Diseases, 22nd Century Medical and Research Center, The University of Tokyo, Tokyo 113-0033, Japan [3] Department of Molecular Medicinal Sciences on Metabolic Regulation, 22nd Century Medical and Research Center, The University of Tokyo, Tokyo 113-0033, Japan [4].〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24172895" target="_blank"〉PubMed〈/a〉
    Keywords: Adenylate Kinase/metabolism ; Adiponectin/metabolism/pharmacology ; Adipose Tissue, White/drug effects/metabolism/pathology ; Administration, Oral ; Animals ; Diabetes Mellitus, Type 2/complications/*drug therapy/metabolism/prevention & ; control ; Diet, High-Fat ; Drug Evaluation, Preclinical ; Dyslipidemias/drug therapy ; Enzyme Activation/drug effects ; Glucose Intolerance/drug therapy ; Inflammation/drug therapy ; Insulin Resistance ; Liver/drug effects/metabolism/pathology ; Longevity/*drug effects ; Mice ; Mitochondria/drug effects/metabolism ; Muscle Fibers, Skeletal/cytology/drug effects ; Muscles/cytology ; Obesity/complications/drug therapy/genetics/*physiopathology ; Oxidative Stress/drug effects ; PPAR alpha/metabolism ; Piperidines/administration & dosage/metabolism/*pharmacology/therapeutic use ; Receptors, Adiponectin/*agonists/deficiency/genetics/metabolism ; Signal Transduction/drug effects ; Small Molecule Libraries/chemistry ; Transcription Factors/biosynthesis ; Triglycerides/metabolism
    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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  • 9
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    The selective tRNA aminoacylation mechanism based on a single G*U pair (2014)
    Nature Publishing Group (NPG)
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    Publication Date: 2014-06-12
    Description: Ligation of tRNAs with their cognate amino acids, by aminoacyl-tRNA synthetases, establishes the genetic code. Throughout evolution, tRNA(Ala) selection by alanyl-tRNA synthetase (AlaRS) has depended predominantly on a single wobble base pair in the acceptor stem, G3*U70, mainly on the kcat level. Here we report the crystal structures of an archaeal AlaRS in complex with tRNA(Ala) with G3*U70 and its A3*U70 variant. AlaRS interacts with both the minor- and the major-groove sides of G3*U70, widening the major groove. The geometry difference between G3*U70 and A3*U70 is transmitted along the acceptor stem to the 3'-CCA region. Thus, the 3'-CCA region of tRNA(Ala) with G3*U70 is oriented to the reactive route that reaches the active site, whereas that of the A3*U70 variant is folded back into the non-reactive route. This novel mechanism enables the single wobble pair to dominantly determine the specificity of tRNA selection, by an approximate 100-fold difference in kcat.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4323281/" 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/PMC4323281/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Naganuma, Masahiro -- Sekine, Shun-ichi -- Chong, Yeeting Esther -- Guo, Min -- Yang, Xiang-Lei -- Gamper, Howard -- Hou, Ya-Ming -- Schimmel, Paul -- Yokoyama, Shigeyuki -- GM015539/GM/NIGMS NIH HHS/ -- GM023562/GM/NIGMS NIH HHS/ -- NS085092/NS/NINDS NIH HHS/ -- R01 GM015539/GM/NIGMS NIH HHS/ -- R01 GM023562/GM/NIGMS NIH HHS/ -- R01 GM100136/GM/NIGMS NIH HHS/ -- R01 NS085092/NS/NINDS NIH HHS/ -- England -- Nature. 2014 Jun 26;510(7506):507-11. doi: 10.1038/nature13440. Epub 2014 Jun 11.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] RIKEN Systems and Structural Biology Center, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan [2] Department of Biophysics and Biochemistry and Laboratory of Structural Biology, Graduate School of Science, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan [3] RIKEN Structural Biology Laboratory, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan. ; 1] RIKEN Systems and Structural Biology Center, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan [2] Department of Biophysics and Biochemistry and Laboratory of Structural Biology, Graduate School of Science, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan [3] Division of Structural and Synthetic Biology, RIKEN Center for Life Science Technologies, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan. ; 1] The Skaggs Institute for Chemical Biology and the Department of Cell and Molecular Biology, The Scripps Research Institute, BCC-379, 10550 North Torrey Pines Road, La Jolla, California 92037, USA [2] aTyr Pharma, 3545 John Hopkins Court, San Diego, California 92121, USA (Y.E.C.); Department of Cancer Biology, The Scripps Research Institute, 130 Scripps Way, Jupiter, Florida 33458, USA (M.G.). ; The Skaggs Institute for Chemical Biology and the Department of Cell and Molecular Biology, The Scripps Research Institute, BCC-379, 10550 North Torrey Pines Road, La Jolla, California 92037, USA. ; Department of Biochemistry and Molecular Biology, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA. ; 1] The Skaggs Institute for Chemical Biology and the Department of Cell and Molecular Biology, The Scripps Research Institute, BCC-379, 10550 North Torrey Pines Road, La Jolla, California 92037, USA [2] The Scripps Florida Research Institute, 130 Scripps Way, 3B3 Jupiter, Florida 33458-5284, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24919148" target="_blank"〉PubMed〈/a〉
    Keywords: Adenosine Monophosphate/analogs & derivatives/chemistry ; Alanine-tRNA Ligase/*chemistry ; Archaeoglobus fulgidus/*enzymology/*genetics ; *Base Pairing ; Base Sequence ; Catalytic Domain ; Crystallography, X-Ray ; Kinetics ; Models, Molecular ; RNA, Transfer, Ala/*chemistry/*genetics ; Substrate Specificity ; *Transfer RNA Aminoacylation
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 10
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    A novel recurrent mutation in MITF predisposes to familial and sporadic melanoma (2011)
    Nature Publishing Group (NPG)
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    Publication Date: 2011-11-15
    Description: So far, two genes associated with familial melanoma have been identified, accounting for a minority of genetic risk in families. Mutations in CDKN2A account for approximately 40% of familial cases, and predisposing mutations in CDK4 have been reported in a very small number of melanoma kindreds. Here we report the whole-genome sequencing of probands from several melanoma families, which we performed in order to identify other genes associated with familial melanoma. We identify one individual carrying a novel germline variant (coding DNA sequence c.G1075A; protein sequence p.E318K; rs149617956) in the melanoma-lineage-specific oncogene microphthalmia-associated transcription factor (MITF). Although the variant co-segregated with melanoma in some but not all cases in the family, linkage analysis of 31 families subsequently identified to carry the variant generated a log of odds (lod) score of 2.7 under a dominant model, indicating E318K as a possible intermediate risk variant. Consistent with this, the E318K variant was significantly associated with melanoma in a large Australian case-control sample. Likewise, it was similarly associated in an independent case-control sample from the United Kingdom. In the Australian sample, the variant allele was significantly over-represented in cases with a family history of melanoma, multiple primary melanomas, or both. The variant allele was also associated with increased naevus count and non-blue eye colour. Functional analysis of E318K showed that MITF encoded by the variant allele had impaired sumoylation and differentially regulated several MITF targets. These data indicate that MITF is a melanoma-predisposition gene and highlight the utility of whole-genome sequencing to identify novel rare variants associated with disease susceptibility.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3266855/" 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/PMC3266855/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Yokoyama, Satoru -- Woods, Susan L -- Boyle, Glen M -- Aoude, Lauren G -- MacGregor, Stuart -- Zismann, Victoria -- Gartside, Michael -- Cust, Anne E -- Haq, Rizwan -- Harland, Mark -- Taylor, John C -- Duffy, David L -- Holohan, Kelly -- Dutton-Regester, Ken -- Palmer, Jane M -- Bonazzi, Vanessa -- Stark, Mitchell S -- Symmons, Judith -- Law, Matthew H -- Schmidt, Christopher -- Lanagan, Cathy -- O'Connor, Linda -- Holland, Elizabeth A -- Schmid, Helen -- Maskiell, Judith A -- Jetann, Jodie -- Ferguson, Megan -- Jenkins, Mark A -- Kefford, Richard F -- Giles, Graham G -- Armstrong, Bruce K -- Aitken, Joanne F -- Hopper, John L -- Whiteman, David C -- Pharoah, Paul D -- Easton, Douglas F -- Dunning, Alison M -- Newton-Bishop, Julia A -- Montgomery, Grant W -- Martin, Nicholas G -- Mann, Graham J -- Bishop, D Timothy -- Tsao, Hensin -- Trent, Jeffrey M -- Fisher, David E -- Hayward, Nicholas K -- Brown, Kevin M -- 10118/Cancer Research UK/United Kingdom -- 10589/Cancer Research UK/United Kingdom -- AR043369-14/AR/NIAMS NIH HHS/ -- C490/A11021/Cancer Research UK/United Kingdom -- C588/A10589/Cancer Research UK/United Kingdom -- C588/A4994/Cancer Research UK/United Kingdom -- C8197/A10123/Cancer Research UK/United Kingdom -- C8216/A6129/Cancer Research UK/United Kingdom -- CA88363/CA/NCI NIH HHS/ -- K24CA149202/CA/NCI NIH HHS/ -- P50CA9368/CA/NCI NIH HHS/ -- R01 AR043369/AR/NIAMS NIH HHS/ -- R01 CA-83115-01A2/CA/NCI NIH HHS/ -- R01 CA088363/CA/NCI NIH HHS/ -- R01 CA088363-09/CA/NCI NIH HHS/ -- R01 CA83115/CA/NCI NIH HHS/ -- England -- Nature. 2011 Nov 13;480(7375):99-103. doi: 10.1038/nature10630.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Dermatology, Cutaneous Biology Research Center, Massachusetts General Hospital, Harvard Medical School, Massachusetts 02114, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22080950" target="_blank"〉PubMed〈/a〉
    Keywords: Adult ; Aged ; Aged, 80 and over ; Female ; Gene Expression Regulation, Neoplastic ; *Genetic Predisposition to Disease ; Humans ; Male ; Melanoma/*genetics ; Microphthalmia-Associated Transcription Factor/*genetics ; Middle Aged ; *Mutation ; Sumoylation/genetics ; Young Adult
    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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