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Author Kerr, G.; Sheldon, H.; Chaikuad, A.; Alfano, I.; Delft, F. von; Bullock, A.N.; Harris, A.L. openurl 
  Title A small molecule targeting ALK1 prevents Notch cooperativity and inhibits functional angiogenesis Type Journal Article
  Year 2015 Publication Abbreviated Journal Angiogenesis  
  Volume 18 Issue 2 Pages 209--217  
  Keywords Type II,Chick Embryo,Growth Differentiation Factor 2,Growth Differentiation Factors,Human Umbilical Vein Endothelial Cells,Humans,Neovascularization,Physiologic,Phenols,Protein Kinase Inhibitors,Receptors,Notch  
  Abstract Activin receptor-like kinase 1 (ALK1, encoded by the gene ACVRL1) is a type I BMP/TGF-ß receptor that mediates signalling in endothelial cells via phosphorylation of SMAD1/5/8. During angiogenesis, sprouting endothelial cells specialise into tip cells and stalk cells. ALK1 synergises with Notch in stalk cells to induce expression of the Notch targets HEY1 and HEY2 and thereby represses tip cell formation and angiogenic sprouting. The ALK1-Fc soluble protein fusion has entered clinic trials as a therapeutic strategy to sequester the high-affinity extracellular ligand BMP9. Here, we determined the crystal structure of the ALK1 intracellular kinase domain and explored the effects of a small molecule kinase inhibitor K02288 on angiogenesis. K02288 inhibited BMP9-induced phosphorylation of SMAD1/5/8 in human umbilical vein endothelial cells to reduce both the SMAD and the Notch-dependent transcriptional responses. In endothelial sprouting assays, K02288 treatment induced a hypersprouting phenotype reminiscent of Notch inhibition. Furthermore, K02288 caused dysfunctional vessel formation in a chick chorioallantoic membrane assay of angiogenesis. Such activity may be advantageous for small molecule inhibitors currently in preclinical development for specific BMP gain of function conditions, including diffuse intrinsic pontine glioma and fibrodysplasia ossificans progressiva, as well as more generally for other applications in tumour biology.  
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  Series Editor Series Title Abbreviated Series Title  
  Series Volume Series Issue Edition  
  ISSN 1573-7209 ISBN Medium  
  Area Expedition Conference  
  Notes Approved no  
  Call Number (up) AG @ matthewjvarga @ Serial 46992  
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Author Wu, H.; Zeng, H.; Lam, R.; Tempel, W.; Kerr, I.D.; Min, J. url  openurl
  Title Structure of the human MLH1 N-terminus: implications for predisposition to Lynch syndrome Type Journal Article
  Year 2015 Publication Abbreviated Journal Acta Crystallogr F Struct Biol Commun  
  Volume 71 Issue 26249686 Pages 981--985  
  Keywords structural biology,variant assessment,pdb  
  Abstract Mismatch repair prevents the accumulation of erroneous insertions/deletions and non-Watson-Crick base pairs in the genome. Pathogenic mutations in the MLH1 gene are associated with a predisposition to Lynch and Turcot’s syndromes. Although genetic testing for these mutations is available, robust classification of variants requires strong clinical and functional support. Here, the first structure of the N-terminus of human MLH1, determined by X-ray crystallography, is described. The structure shares a high degree of similarity with previously determined prokaryotic MLH1 homologs; however, this structure affords a more accurate platform for the classification of MLH1 variants.  
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  Series Editor Series Title Abbreviated Series Title  
  Series Volume Series Issue Edition  
  ISSN 2053-230x ISBN Medium  
  Area Expedition Conference  
  Notes Approved no  
  Call Number (up) AG @ matthewjvarga @ Serial 47007  
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Author Choi, Y.; Chan, A.P. openurl 
  Title PROVEAN web server: a tool to predict the functional effect of amino acid substitutions and indels Type Journal Article
  Year 2015 Publication Abbreviated Journal Bioinformatics  
  Volume 31 Issue 16 Pages 2745--2747  
  Keywords bioinformatics,variant assessment,in silico tool  
  Abstract Summary: We present a web server to predict the functional effect of single or multiple amino acid substitutions, insertions and deletions using the prediction tool PROVEAN. The server provides rapid analysis of protein variants from any organisms, and also supports high-throughput analysis for human and mouse variants at both the genomic and protein levels.Availability and implementation: The web server is freely available and open to all users with no login requirements at http://provean.jcvi.org.Contact:achan@jcvi.orgSupplementary information:Supplementary data are available at Bioinformatics online.  
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  Series Editor Series Title Abbreviated Series Title  
  Series Volume Series Issue Edition  
  ISSN 1367-4803 ISBN Medium  
  Area Expedition Conference  
  Notes Approved no  
  Call Number (up) AG @ matthewjvarga @ Serial 47017  
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Author Frappier, V.; Najmanovich, R. url  openurl
  Title Vibrational entropy differences between mesophile and thermophile proteins and their use in protein engineering Type Journal Article
  Year 2015 Publication Abbreviated Journal Protein Science  
  Volume 24 Issue 25367089 Pages 474--483  
  Keywords flexibility project,method  
  Abstract We recently introduced ENCoM, an elastic network atomic contact model, as the first coarse-grained normal mode analysis method that accounts for the nature of amino acids and can predict the effect of mutations on thermostability based on changes vibrational entropy. In this proof-of-concept article, we use pairs of mesophile and thermophile homolog proteins with identical structures to determine if a measure of vibrational entropy based on normal mode analysis can discriminate thermophile from mesophile proteins. We observe that in around 60\% of cases, thermophile proteins are more rigid at equivalent temperatures than their mesophile counterpart and this difference can guide the design of proteins to increase their thermostability through series of mutations. We observe that mutations separating thermophile proteins from their mesophile orthologs contribute independently to a decrease in vibrational entropy and discuss the application and implications of this methodology to protein engineering.  
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  Series Editor Series Title Abbreviated Series Title  
  Series Volume Series Issue Edition  
  ISSN 0961-8368 ISBN Medium  
  Area Expedition Conference  
  Notes Approved no  
  Call Number (up) AG @ matthewjvarga @ Serial 47019  
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Author Cajigas, I.; Leib, D.E.; Cochrane, J.; Luo, H.; Swyter, K.R.; Chen, S.; Clark, B.S.; Thompson, J.; Yates, J.R.; Kingston, R.E.; Kohtz, J.D. openurl 
  Title Evf2 lncRNA/BRG1/DLX1 interactions reveal RNA-dependent inhibition of chromatin remodeling Type Journal Article
  Year 2015 Publication Abbreviated Journal Development (Cambridge, England)  
  Volume 142 Issue 15 Pages 2641--2652  
  Keywords  
  Abstract Transcription-regulating long non-coding RNAs (lncRNAs) have the potential to control the site-specific expression of thousands of target genes. Previously, we showed that Evf2, the first described ultraconserved lncRNA, increases the association of transcriptional activators (DLX homeodomain proteins) with key DNA enhancers but represses gene expression. In this report, mass spectrometry shows that the Evf2-DLX1 ribonucleoprotein (RNP) contains the SWI/SNF-related chromatin remodelers Brahma-related gene 1 (BRG1, SMARCA4) and Brahma-associated factor (BAF170, SMARCC2) in the developing mouse forebrain. Evf2 RNA colocalizes with BRG1 in nuclear clouds and increases BRG1 association with key DNA regulatory enhancers in the developing forebrain. While BRG1 directly interacts with DLX1 and Evf2 through distinct binding sites, Evf2 directly inhibits BRG1 ATPase and chromatin remodeling activities. In vitro studies show that both RNA-BRG1 binding and RNA inhibition of BRG1 ATPase/remodeling activity are promiscuous, suggesting that context is a crucial factor in RNA-dependent chromatin remodeling inhibition. Together, these experiments support a model in which RNAs convert an active enhancer to a repressed enhancer by directly inhibiting chromatin remodeling activity, and address the apparent paradox of RNA-mediated stabilization of transcriptional activators at enhancers with a repressive outcome. The importance of BRG1/RNA and BRG1/homeodomain interactions in neurodevelopmental disorders is underscored by the finding that mutations in Coffin-Siris syndrome, a human intellectual disability disorder, localize to the BRG1 RNA-binding and DLX1-binding domains.  
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  Series Editor Series Title Abbreviated Series Title  
  Series Volume Series Issue Edition  
  ISSN 1477-9129 ISBN Medium  
  Area Expedition Conference  
  Notes Approved no  
  Call Number (up) AG @ matthewjvarga @ Serial 47024  
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Author Allen, M.D.; Freund, S.M.V.; Zinzalla, G.; Bycroft, M. openurl 
  Title The SWI/SNF Subunit INI1 Contains an N-Terminal Winged Helix DNA Binding Domain that Is a Target for Mutations in Schwannomatosis Type Journal Article
  Year 2015 Publication Abbreviated Journal Structure (London, England : 1993)  
  Volume 23 Issue 7 Pages 1344--1349  
  Keywords Non-Histone,genetics; Conserved Sequence; DNA-Binding Proteins,genetics; Humans; Models,Molecular; Molecular Sequence Data; Mutation; Neurilemmoma,genetics; Neurofibromatoses,genetics; Nuclear Magnetic Resonance,Biomolecular; Protein Binding; Protein Interaction Domains and Motifs; Protein Structure,Secondary; SMARCB1 Protein; Skin Neoplasms,genetics; Transcription Factors,genetics  
  Abstract SWI/SNF complexes use the energy of ATP hydrolysis to remodel chromatin. In mammals they play a central role in regulating gene expression during differentiation and proliferation. Mutations in SWI/SNF subunits are among the most frequent gene alterations in cancer. The INI1/hSNF5/SMARCB1 subunit is mutated in both malignant rhabdoid tumor, a highly aggressive childhood cancer, and schwannomatosis, a tumor-predisposing syndrome characterized by mostly benign tumors of the CNS. Here, we show that mutations in INI1 that cause schwannomatosis target a hitherto unidentified N-terminal winged helix DNA binding domain that is also present in the BAF45a/PHF10 subunit of the SWI/SNF complex. The domain is structurally related to the SKI/SNO/DAC domain, which is found in a number of metazoan chromatin-associated proteins.  
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  Series Volume Series Issue Edition  
  ISSN 1878-4186 ISBN Medium  
  Area Expedition Conference  
  Notes Approved no  
  Call Number (up) AG @ matthewjvarga @ Serial 47059  
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Author Saito, Y.; Komatsu, K. openurl 
  Title Functional Role of NBS1 in Radiation Damage Response and Translesion DNA Synthesis Type Journal Article
  Year 2015 Publication Abbreviated Journal Biomolecules  
  Volume 5 Issue 3 Pages 1990--2002  
  Keywords chemistry,metabolism; Chromatin Assembly and Disassembly,drug effects,radiation effects; DNA,biosynthesis,genetics; DNA Damage; Homologous Recombination,radiation effects; Humans; Nuclear Proteins,metabolism; Radiation; DNA repair; NBS1; chromatin remodeling; homologous recombination; translesion DNA synthesis  
  Abstract Nijmegen breakage syndrome (NBS) is a recessive genetic disorder characterized by increased sensitivity to ionizing radiation (IR) and a high frequency of malignancies. NBS1, a product of the mutated gene in NBS, contains several protein interaction domains in the N-terminus and C-terminus. The C-terminus of NBS1 is essential for interactions with MRE11, a homologous recombination repair nuclease, and ATM, a key player in signal transduction after the generation of DNA double-strand breaks (DSBs), which is induced by IR. Moreover, NBS1 regulates chromatin remodeling during DSB repair by histone H2B ubiquitination through binding to RNF20 at the C-terminus. Thus, NBS1 is considered as the first protein to be recruited to DSB sites, wherein it acts as a sensor or mediator of DSB damage responses. In addition to DSB response, we showed that NBS1 initiates Polη-dependent translesion DNA synthesis by recruiting RAD18 through its binding at the NBS1 C-terminus after UV exposure, and it also functions after the generation of interstrand crosslink DNA damage. Thus, NBS1 has multifunctional roles in response to DNA damage from a variety of genotoxic agents, including IR.  
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  Series Volume Series Issue Edition  
  ISSN 2218-273x ISBN Medium  
  Area Expedition Conference  
  Notes Approved no  
  Call Number (up) AG @ matthewjvarga @ Serial 47070  
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Author Frappier, V.; Chartier, M.; Najmanovich, R.J. url  openurl
  Title ENCoM server: exploring protein conformational space and the effect of mutations on protein function and stability Type Journal Article
  Year 2015 Publication Abbreviated Journal Nucleic Acids Research  
  Volume 43 Issue 25883149 Pages W395--W400  
  Keywords flexibility project,method  
  Abstract ENCoM is a coarse-grained normal mode analysis method recently introduced that unlike previous such methods is unique in that it accounts for the nature of amino acids. The inclusion of this layer of information was shown to improve conformational space sampling and apply for the first time a coarse-grained normal mode analysis method to predict the effect of single point mutations on protein dynamics and thermostability resulting from vibrational entropy changes. Here we present a web server that allows non-technical users to have access to ENCoM calculations to predict the effect of mutations on thermostability and dynamics as well as to generate geometrically realistic conformational ensembles. The server is accessible at: http://bcb.med.usherbrooke.ca/encom.  
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  Series Volume Series Issue Edition  
  ISSN 0305-1048 ISBN Medium  
  Area Expedition Conference  
  Notes Approved no  
  Call Number (up) AG @ matthewjvarga @ Serial 47093  
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Author Richards, S.; Aziz, N.; Bale, S.; Bick, D.; Das, S.; Gastier-Foster, J.; Grody, W.W.; Hegde, M.; Lyon, E.; Spector, E.; Voelkerding, K.; Rehm, H.L. url  openurl
  Title Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology Type Journal Article
  Year 2015 Publication Abbreviated Journal Genetics In Medicine  
  Volume 17 Issue Pages 405  
  Keywords guidelines  
  Abstract  
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  Series Volume Series Issue Edition  
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  Area Expedition Conference  
  Notes Approved no  
  Call Number (up) AG @ matthewjvarga @ Serial 47096  
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Author Strøm, T.B.; Laerdahl, J.K.; Leren, T.P. openurl 
  Title Mutation p.L799R in the LDLR, which affects the transmembrane domain of the LDLR, prevents membrane insertion and causes secretion of the mutant LDLR Type Journal Article
  Year 2015 Publication Abbreviated Journal Human Molecular Genetics  
  Volume 24 Issue 20 Pages 5836-5844  
  Keywords gene:LDLR  
  Abstract Mutations in the low-density lipoprotein receptor (LDLR) gene cause familial hypercholesterolemia (FH). The mechanism by which mutations in the LDLR affecting the transmembrane domain of the receptor cause FH has not been thoroughly investigated. In this study, we have selected 12 naturally occurring mutations affecting the transmembrane domain and studied their effect on the LDLR. The main strategy has been to transiently transfect HepG2 cells with mutant LDLR plasmids and to study the mutant LDLRs in cell lysates and in media by western blot analysis. The most striking finding was that mutation p.L799R led to secretion of the entire 160 kDa mature L799R-LDLR. Residue 799Leu is in the middle of the 22-residue transmembrane domain, and introduction of a basic residue in the hydrophobic core of the transmembrane domain could prevent L799R-LDLR from being correctly recognized and integrated in the membrane by the Sec61 translocon complex. This would then lead to translocation of the entire L799R-LDLR into the lumen of the endoplasmic reticulum. Mutation p.L799R should be considered a member of a separate class of FH-causing mutations that affects the insertion of the LDLR in the cell membrane.  
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  Series Editor Series Title Abbreviated Series Title  
  Series Volume Series Issue Edition  
  ISSN 0964-6906 ISBN Medium  
  Area Expedition Conference  
  Notes Approved no  
  Call Number (up) AG @ matthewjvarga @ Serial 47097  
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