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  • 1
    Publication Date: 2014-07-22
    Description: In the 1950s, the drug thalidomide, administered as a sedative to pregnant women, led to the birth of thousands of children with multiple defects. Despite the teratogenicity of thalidomide and its derivatives lenalidomide and pomalidomide, these immunomodulatory drugs (IMiDs) recently emerged as effective treatments for multiple myeloma and 5q-deletion-associated dysplasia. IMiDs target the E3 ubiquitin ligase CUL4-RBX1-DDB1-CRBN (known as CRL4(CRBN)) and promote the ubiquitination of the IKAROS family transcription factors IKZF1 and IKZF3 by CRL4(CRBN). Here we present crystal structures of the DDB1-CRBN complex bound to thalidomide, lenalidomide and pomalidomide. The structure establishes that CRBN is a substrate receptor within CRL4(CRBN) and enantioselectively binds IMiDs. Using an unbiased screen, we identified the homeobox transcription factor MEIS2 as an endogenous substrate of CRL4(CRBN). Our studies suggest that IMiDs block endogenous substrates (MEIS2) from binding to CRL4(CRBN) while the ligase complex is recruiting IKZF1 or IKZF3 for degradation. This dual activity implies that small molecules can modulate an E3 ubiquitin ligase and thereby upregulate or downregulate the ubiquitination of proteins.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4423819/" 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/PMC4423819/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Fischer, Eric S -- Bohm, Kerstin -- Lydeard, John R -- Yang, Haidi -- Stadler, Michael B -- Cavadini, Simone -- Nagel, Jane -- Serluca, Fabrizio -- Acker, Vincent -- Lingaraju, Gondichatnahalli M -- Tichkule, Ritesh B -- Schebesta, Michael -- Forrester, William C -- Schirle, Markus -- Hassiepen, Ulrich -- Ottl, Johannes -- Hild, Marc -- Beckwith, Rohan E J -- Harper, J Wade -- Jenkins, Jeremy L -- Thoma, Nicolas H -- AG011085/AG/NIA NIH HHS/ -- R01 AG011085/AG/NIA NIH HHS/ -- England -- Nature. 2014 Aug 7;512(7512):49-53. doi: 10.1038/nature13527. Epub 2014 Jul 16.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, CH-4058 Basel, Switzerland [2] University of Basel, Petersplatz 10, CH-4003 Basel, Switzerland. ; Department of Cell Biology, Harvard Medical School, 240 Longwood Avenue, Boston, Massachusetts 02115, USA. ; Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA. ; 1] Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, CH-4058 Basel, Switzerland [2] University of Basel, Petersplatz 10, CH-4003 Basel, Switzerland [3] Swiss Institute of Bioinformatics, Maulbeerstrasse 66, CH-4058 Basel, Switzerland. ; Novartis Pharma AG, Institutes for Biomedical Research, Novartis Campus, CH-4056 Basel, Switzerland.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25043012" target="_blank"〉PubMed〈/a〉
    Keywords: Crystallography, X-Ray ; DNA-Binding Proteins/agonists/antagonists & inhibitors/chemistry/metabolism ; Homeodomain Proteins/metabolism ; Humans ; Models, Molecular ; Multiprotein Complexes/agonists/antagonists & inhibitors/chemistry/metabolism ; Peptide Hydrolases/*chemistry/metabolism ; Protein Binding ; Structure-Activity Relationship ; Substrate Specificity ; Thalidomide/analogs & derivatives/*chemistry/metabolism ; Transcription Factors/metabolism ; Ubiquitin-Protein Ligases/antagonists & inhibitors/*chemistry/metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 2
    Publication Date: 2015-02-18
    Description: In mammalian nucleotide excision repair, the DDB1–DDB2 complex recognizes UV-induced DNA photolesions and facilitates recruitment of the XPC complex. Upon binding to damaged DNA, the Cullin 4 ubiquitin ligase associated with DDB1–DDB2 is activated and ubiquitinates DDB2 and XPC. The structurally disordered N-terminal tail of DDB2 contains seven lysines identified as major sites for ubiquitination that target the protein for proteasomal degradation; however, the precise biological functions of these modifications remained unknown. By exogenous expression of mutant DDB2 proteins in normal human fibroblasts, here we show that the N-terminal tail of DDB2 is involved in regulation of cellular responses to UV. By striking contrast with behaviors of exogenous DDB2, the endogenous DDB2 protein was stabilized even after UV irradiation as a function of the XPC expression level. Furthermore, XPC competitively suppressed ubiquitination of DDB2 in vitro , and this effect was significantly promoted by centrin-2, which augments the DNA damage-recognition activity of XPC. Based on these findings, we propose that in cells exposed to UV, DDB2 is protected by XPC from ubiquitination and degradation in a stochastic manner; thus XPC allows DDB2 to initiate multiple rounds of repair events, thereby contributing to the persistence of cellular DNA repair capacity.
    Print ISSN: 0305-1048
    Electronic ISSN: 1362-4962
    Topics: Biology
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  • 3
    Publication Date: 2016-04-01
    Description: The cullin-RING ubiquitin E3 ligase (CRL) family comprises over 200 members in humans. The COP9 signalosome complex (CSN) regulates CRLs by removing their ubiquitin-like activator NEDD8. The CUL4A-RBX1-DDB1-DDB2 complex (CRL4A(DDB2)) monitors the genome for ultraviolet-light-induced DNA damage. CRL4A(DBB2) is inactive in the absence of damaged DNA and requires CSN to regulate the repair process. The structural basis of CSN binding to CRL4A(DDB2) and the principles of CSN activation are poorly understood. Here we present cryo-electron microscopy structures for CSN in complex with neddylated CRL4A ligases to 6.4 A resolution. The CSN conformers defined by cryo-electron microscopy and a novel apo-CSN crystal structure indicate an induced-fit mechanism that drives CSN activation by neddylated CRLs. We find that CSN and a substrate cannot bind simultaneously to CRL4A, favouring a deneddylated, inactive state for substrate-free CRL4 complexes. These architectural and regulatory principles appear conserved across CRL families, allowing global regulation by CSN.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Cavadini, Simone -- Fischer, Eric S -- Bunker, Richard D -- Potenza, Alessandro -- Lingaraju, Gondichatnahalli M -- Goldie, Kenneth N -- Mohamed, Weaam I -- Faty, Mahamadou -- Petzold, Georg -- Beckwith, Rohan E J -- Tichkule, Ritesh B -- Hassiepen, Ulrich -- Abdulrahman, Wassim -- Pantelic, Radosav S -- Matsumoto, Syota -- Sugasawa, Kaoru -- Stahlberg, Henning -- Thoma, Nicolas H -- England -- Nature. 2016 Mar 31;531(7596):598-603. doi: 10.1038/nature17416.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, 4058 Basel, Switzerland. ; University of Basel, Petersplatz 10, 4003 Basel, Switzerland. ; Department of Cancer Biology, Dana-Farber Cancer Institute, LC-4312, 360 Longwood Avenue, Boston, Massachusetts 02215, USA. ; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02215, USA. ; Center for Cellular Imaging and NanoAnalytics, Biozentrum, University of Basel, 4058 Basel, Switzerland. ; Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA. ; Novartis Pharma AG, Institutes for Biomedical Research, Novartis Campus, 4056 Basel, Switzerland. ; Gatan R&D, 5974 W. Las Positas Boulevard, Pleasanton, California 94588, USA. ; Biosignal Research Center, Organization of Advanced Science and Technology, Kobe University, Kobe 657-8501, Japan. ; Graduate School of Science, Kobe University, Kobe, 657-8501, Japan.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/27029275" target="_blank"〉PubMed〈/a〉
    Keywords: Allosteric Regulation ; Apoproteins/chemistry/metabolism/ultrastructure ; Binding Sites ; *Biocatalysis ; Carrier Proteins/chemistry/metabolism/ultrastructure ; Cryoelectron Microscopy ; Crystallography, X-Ray ; Cullin Proteins/chemistry/metabolism/ultrastructure ; DNA Damage ; DNA-Binding Proteins/chemistry/metabolism/ultrastructure ; Humans ; Kinetics ; Models, Molecular ; Multiprotein Complexes/chemistry/*metabolism/*ultrastructure ; Peptide Hydrolases/chemistry/*metabolism/*ultrastructure ; Protein Binding ; Ubiquitination ; Ubiquitins/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
    Publication Date: 2014-07-22
    Description: Ubiquitination is a crucial cellular signalling process, and is controlled on multiple levels. Cullin-RING E3 ubiquitin ligases (CRLs) are regulated by the eight-subunit COP9 signalosome (CSN). CSN inactivates CRLs by removing their covalently attached activator, NEDD8. NEDD8 cleavage by CSN is catalysed by CSN5, a Zn(2+)-dependent isopeptidase that is inactive in isolation. Here we present the crystal structure of the entire approximately 350-kDa human CSN holoenzyme at 3.8 A resolution, detailing the molecular architecture of the complex. CSN has two organizational centres: a horseshoe-shaped ring created by its six proteasome lid-CSN-initiation factor 3 (PCI) domain proteins, and a large bundle formed by the carboxy-terminal alpha-helices of every subunit. CSN5 and its dimerization partner, CSN6, are intricately embedded at the core of the helical bundle. In the substrate-free holoenzyme, CSN5 is autoinhibited, which precludes access to the active site. We find that neddylated CRL binding to CSN is sensed by CSN4, and communicated to CSN5 with the assistance of CSN6, resulting in activation of the deneddylase.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lingaraju, Gondichatnahalli M -- Bunker, Richard D -- Cavadini, Simone -- Hess, Daniel -- Hassiepen, Ulrich -- Renatus, Martin -- Fischer, Eric S -- Thoma, Nicolas H -- England -- Nature. 2014 Aug 14;512(7513):161-5. doi: 10.1038/nature13566. Epub 2014 Jul 16.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, 4058 Basel, Switzerland [2] University of Basel, Petersplatz 10, 4003 Basel, Switzerland [3]. ; 1] Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, 4058 Basel, Switzerland [2] University of Basel, Petersplatz 10, 4003 Basel, Switzerland. ; Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, 4058 Basel, Switzerland. ; Novartis Pharma AG, Institutes for Biomedical Research, Novartis Campus, 4056 Basel, Switzerland.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25043011" target="_blank"〉PubMed〈/a〉
    Keywords: Adaptor Proteins, Signal Transducing ; Catalytic Domain ; Crystallography, X-Ray ; Enzyme Activation ; Humans ; Intracellular Signaling Peptides and Proteins/metabolism ; *Models, Molecular ; Multiprotein Complexes/*chemistry ; Peptide Hydrolases/*chemistry/metabolism ; Protein Binding ; Protein Structure, Tertiary ; Transcription Factors/metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 5
    Publication Date: 2016-02-26
    Description: Thalidomide and its derivatives, lenalidomide and pomalidomide, are immune modulatory drugs (IMiDs) used in the treatment of haematologic malignancies. IMiDs bind CRBN, the substrate receptor of the CUL4-RBX1-DDB1-CRBN (also known as CRL4(CRBN)) E3 ubiquitin ligase, and inhibit ubiquitination of endogenous CRL4(CRBN) substrates. Unexpectedly, IMiDs also repurpose the ligase to target new proteins for degradation. Lenalidomide induces degradation of the lymphoid transcription factors Ikaros and Aiolos (also known as IKZF1 and IKZF3), and casein kinase 1alpha (CK1alpha), which contributes to its clinical efficacy in the treatment of multiple myeloma and 5q-deletion associated myelodysplastic syndrome (del(5q) MDS), respectively. How lenalidomide alters the specificity of the ligase to degrade these proteins remains elusive. Here we present the 2.45 A crystal structure of DDB1-CRBN bound to lenalidomide and CK1alpha. CRBN and lenalidomide jointly provide the binding interface for a CK1alpha beta-hairpin-loop located in the kinase N-lobe. We show that CK1alpha binding to CRL4(CRBN) is strictly dependent on the presence of an IMiD. Binding of IKZF1 to CRBN similarly requires the compound and both, IKZF1 and CK1alpha, use a related binding mode. Our study provides a mechanistic explanation for the selective efficacy of lenalidomide in del(5q) MDS therapy. We anticipate that high-affinity protein-protein interactions induced by small molecules will provide opportunities for drug development, particularly for targeted protein degradation.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Petzold, Georg -- Fischer, Eric S -- Thoma, Nicolas H -- England -- Nature. 2016 Apr 7;532(7597):127-30. doi: 10.1038/nature16979. Epub 2016 Feb 24.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, CH-4058 Basel, Switzerland. ; University of Basel, Petersplatz 10, CH-4003 Basel, Switzerland.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26909574" target="_blank"〉PubMed〈/a〉
    Keywords: Binding Sites/drug effects ; Casein Kinase Ialpha/chemistry/*metabolism ; Catalytic Domain ; Crystallography, X-Ray ; Humans ; Ikaros Transcription Factor/chemistry/metabolism ; Models, Molecular ; Protein Binding/drug effects ; Proteolysis/drug effects ; Structure-Activity Relationship ; Substrate Specificity/drug effects ; Thalidomide/*analogs & derivatives/chemistry/metabolism/pharmacology ; Ubiquitin-Protein Ligases/chemistry/*metabolism ; Ubiquitination/drug effects
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 6
    ISSN: 1399-3054
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Biology
    Notes: Accumulation of assimilates in source leaves of magnesium-deficient plants is a well-known feature. We had wished to determine whether metabolite concentrations in sink leaves and roots are affected by magnesium nutrition. Eight-week-old spinach plants were supplied either with a complete nutrient solution (control plants) or with one lacking Mg (deficient plants) for 12 days. Shoot and root fresh weights and dry weights were lower in deficient than in control plants. Mg concentrations in deficient plants were 11% of controls in source leaves, 12% in sink leaves and 26% in roots, respectively. As compared with controls, increases were found in starch and amino acids in source leaves and in sucrose, hexoses, starch and amino acids in sink leaves, whereas they were only slightly enhanced in roots. In phloem sap of magnesium-deficient and control plants no differences in sucrose and amino acid concentrations were found. To prove that sink leaves were the importing organs they were shaded, which did not alter the response to magnesium deficiency as compared with that without shading. Since in the shaded sink leaves the photosynthetic production of metabolites could be excluded, those carbohydrates and amino acids that accumulated in the sink leaves of the deficient plants must have been imported from the source leaves. It is concluded that in magnesium-deficient spinach plants the growth of sink leaves and roots was not limited by carbohydrate or amino acid supply. It is proposed that the accumulation of assimilates in the source leaves of Mg-deficient plants results from a lack of utilization of assimilates in the sink leaves.
    Type of Medium: Electronic Resource
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