title: Structural basis for the recruitment of the human CCR4-NOT deadenylase complex by tristetraprolin.
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' untranslated regions of target mRNAs and subsequently engenders their deadenylation and decay. TTP accomplishes these tasks, at least in part, by recruiting the multisubunit CCR4-NOT deadenylase complex to the mRNA. Here we identify an evolutionarily conserved C-terminal motif in human TTP that directly binds 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, to our knowledge, 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.
authors: Lady Davis Institute for Medical Research, Jewish General Hospital, Montréal, Québec, Canada. marc.fabian@mcgill.ca
authors: Marc R
authors: MR
authors: Fabian
authors: Filipp
authors: F
authors: Frank
authors: Christopher
authors: C
authors: Rouya
authors: Nadeem
authors: N
authors: Siddiqui
authors: Wi S
authors: WS
authors: Lai
authors: Alexey
authors: A
authors: Karetnikov
authors: Perry J
authors: PJ
authors: Blackshear
authors: Bhushan
authors: B
authors: Nagar
authors: Nahum
authors: N
authors: Sonenberg
mesh_terms: D001665:Binding Sites; D018360:Crystallography, X-Ray; D006801:Humans; D008954:Models, Biological; D008958:Models, Molecular; D016297:Mutagenesis, Site-Directed; D050505:Mutant Proteins / Q000737:chemistry / Q000378:metabolism; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2 / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding; D011487:Protein Conformation; D054398:Receptors, CCR4 / Q000737:chemistry* / Q000378:metabolism; D012260:Ribonucleases / Q000737:chemistry* / Q000378:metabolism; D051816:Tristetraprolin / Q000737:chemistry* / Q000378:metabolism
chemical_list: C515354:CCR4 protein, human; D050505:Mutant Proteins; C539882:NR4A2 protein, human; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2; D054398:Receptors, CCR4; D051816:Tristetraprolin; C497552:ZFP36 protein, human; D012260:Ribonucleases; C445084:mRNA deadenylase
references: Front Biosci (Landmark Ed). 2012 Jan 01;17(1):174-88
references: 22201737
references: EMBO J. 2004 Mar 24;23(6):1313-24
references: 15014438
references: Gene. 2012 Jan 15;492(1):42-53
references: 22027279
references: Nat Struct Mol Biol. 2011 Oct 07;18(11):1218-26
references: 21984184
references: Biochem Soc Trans. 2002 Nov;30(Pt 6):945-52
references: 12440952
references: Proc Natl Acad Sci U S A. 2008 Jul 15;105(28):9564-9
references: 18606994
references: Trends Biochem Sci. 2000 Sep;25(9):423-6
references: 10973054
references: J Biol Chem. 1990 Sep 25;265(27):16556-63
references: 2204625
references: Cell. 2012 Aug 3;150(3):563-74
references: 22863009
references: Mol Cell Biol. 2011 Jan;31(2):256-66
references: 21078877
references: J Biol Chem. 2010 Sep 3;285(36):27590-600
references: 20595389
references: Methods Mol Biol. 2004;257:135-54
references: 14770003
references: Nucleic Acids Res. 2011 Jul;39(Web Server issue):W24-8
references: 21602266
references: Nat Rev Mol Cell Biol. 2008 Apr;9(4):337-44
references: 18334997
references: Wiley Interdiscip Rev RNA. 2011 May-Jun;2(3):336-47
references: 21957021
references: Mol Cell. 2012 Oct 26;48(2):207-18
references: 22959269
references: Nucleic Acids Res. 2011 May;39(10):4373-86
references: 21278420
references: Science. 1998 Aug 14;281(5379):1001-5
references: 9703499
references: Wiley Interdiscip Rev RNA. 2011 Jan-Feb;2(1):42-57
references: 21278925
references: Immunity. 1996 May;4(5):445-54
references: 8630730
references: Nucleic Acids Res. 2012 Nov;40(21):11058-72
references: 22977175
references: Annu Rev Biochem. 2010;79:351-79
references: 20533884
references: Genes Dev. 2005 Feb 1;19(3):351-61
references: 15687258
references: Biol Reprod. 2005 Aug;73(2):297-307
references: 15814898
references: J Biol Chem. 2000 Jun 9;275(23):17827-37
references: 10751406
references: Nat Struct Mol Biol. 2011 Oct 07;18(11):1211-7
references: 21984185
references: J Biol Chem. 2004 Mar 12;279(11):10176-84
references: 14688255