20
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: not found

      Structural basis for the recruitment of the human CCR4–NOT deadenylase complex by Tristetraprolin

      research-article

      Read this article at

      ScienceOpenPublisherPMC
      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Tristetraprolin (TTP) is an RNA binding protein that controls the inflammatory response by limiting the expression of several proinflammatory cytokines. TTP post-transcriptionally represses gene expression by interacting with AU-rich elements (AREs) in 3′UTRs of target mRNAs and subsequently engenders their deadenylation and decay. TTP accomplishes these tasks, at least in part, by recruiting the multi subunit CCR4–NOT deadenylase complex to the mRNA. Here we identify an evolutionarily conserved C-terminal motif in human TTP that directly binds to a central domain of CNOT1, a core subunit of the CCR4–NOT complex. A high-resolution crystal structure of the TTP-CNOT1 complex was determined, providing the first structural insight into an ARE-binding protein bound to the CCR4–NOT complex. Mutations at the CNOT1-TTP interface impair TTP-mediated deadenylation, demonstrating the significance of this interaction in TTP-mediated gene silencing.

          Related collections

          Most cited references26

          • Record: found
          • Abstract: found
          • Article: not found

          Substructure solution with SHELXD.

          Iterative dual-space direct methods based on phase refinement in reciprocal space and peak picking in real space are able to locate relatively large numbers of anomalous scatterers efficiently from MAD or SAD data. Truncation of the data at a particular resolution, typically in the range 3.0-3.5 A, can be critical to success. The efficiency can be improved by roughly an order of magnitude by Patterson-based seeding instead of starting from random phases or sites; Patterson superposition methods also provide useful validation. The program SHELXD implementing this approach is available as part of the SHELX package.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            Ulp1-SUMO crystal structure and genetic analysis reveal conserved interactions and a regulatory element essential for cell growth in yeast.

            Modification of cellular proteins by the ubiquitin-like protein SUMO is essential for nuclear processes and cell cycle progression in yeast. The Ulp1 protease catalyzes two essential functions in the SUMO pathway: (1) processing of full-length SUMO to its mature form and (2) deconjugation of SUMO from targeted proteins. Selective reduction of the proteolytic reaction produced a covalent thiohemiacetal transition state complex between a Ulp1 C-terminal fragment and its cellular substrate Smt3, the yeast SUMO homolog. The Ulp1-Smt3 crystal structure and functional testing of elements within the conserved interface elucidate determinants of SUMO recognition, processing, and deconjugation. Genetic analysis guided by the structure further reveals a regulatory element N-terminal to the proteolytic domain that is required for cell growth in yeast.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              A pathogenetic role for TNF alpha in the syndrome of cachexia, arthritis, and autoimmunity resulting from tristetraprolin (TTP) deficiency.

              Tristetraprolin (TTP) is a widely expressed potential transcription factor that contains two unusual CCCH zinc fingers and is encoded by the immediate-early response gene, Zfp-36. Mice made deficient in TTP by gene targeting appeared normal at birth, but soon manifested marked medullary and extramedullary myeloid hyperplasia associated with cachexia, erosive arthritis, dermatitis, conjunctivitis, glomerular mesangial thickening, and high titers of anti-DNA and antinuclear antibodies. Myeloid progenitors from these mice showed no increase in sensitivity to growth factors. Treatment of young TTP-deficient mice with antibodies to tumor necrosis factor alpha (TNF alpha) prevented the development of essentially all aspects of the phenotype. These results indicate a role for TTP in regulating TNF alpha synthesis, secretion, turnover, or action. TTP-deficient mice may serve as useful models of the autoimmune inflammatory state resulting from chronic effective TNF alpha excess.
                Bookmark

                Author and article information

                Journal
                101186374
                31761
                Nat Struct Mol Biol
                Nat. Struct. Mol. Biol.
                Nature structural & molecular biology
                1545-9993
                1545-9985
                2 August 2016
                05 May 2013
                June 2013
                08 August 2016
                : 20
                : 6
                : 735-739
                Affiliations
                [1 ]Lady Davis Institute for Medical Research, SMBD-Jewish General Hospital. Montréal, Quebec, Canada
                [2 ]Department of Oncology, McGill University, Montreal, Quebec, Canada
                [3 ]Department of Biochemistry and Goodman Cancer Centre, McGill University, Montreal, Quebec, Canada
                [4 ]Laboratory of Signal Transduction, National Institute of Environmental Health Science, NC, USA
                Author notes
                Corresponding authors: Marc Fabian ( marc.fabian@ 123456mcgill.ca ), Bhushan Nagar ( bhushan.nagar@ 123456mcgill.ca ), Nahum Sonenberg ( nahum.sonenberg@ 123456mcgill.ca )
                [5]

                These authors contributed equally to this work

                Article
                CAMS4084
                10.1038/nsmb.2572
                4811204
                23644599
                7c33fb73-a48f-4bc2-9b82-b325b40c15e0

                Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms

                History
                Categories
                Article

                Molecular biology
                Molecular biology

                Comments

                Comment on this article