title: Structural basis for the Nanos-mediated recruitment of the CCR4-NOT complex and translational repression.
abstract: The RNA-binding proteins of the Nanos family play an essential role in germ cell development and survival in a wide range of metazoan species. They function by suppressing the expression of target mRNAs through the recruitment of effector complexes, which include the CCR4-NOT deadenylase complex. Here, we show that the three human Nanos paralogs (Nanos1-3) interact with the CNOT1 C-terminal domain and determine the structural basis for the specific molecular recognition. Nanos1-3 bind CNOT1 through a short CNOT1-interacting motif (NIM) that is conserved in all vertebrates and some invertebrate species. The crystal structure of the human Nanos1 NIM peptide bound to CNOT1 reveals that the peptide opens a conserved hydrophobic pocket on the CNOT1 surface by inserting conserved aromatic residues. The substitutions of these aromatic residues in the Nanos1-3 NIMs abolish binding to CNOT1 and abrogate the ability of the proteins to repress translation. Our findings provide the structural basis for the recruitment of the CCR4-NOT complex by vertebrate Nanos, indicate that the NIMs are the major determinants of the translational repression mediated by Nanos, and identify the CCR4-NOT complex as the main effector complex for Nanos function.
authors.affiliation: Department of Biochemistry, Max Planck Institute for Developmental Biology, 72076 Tübingen, Germany.
authors.forename: Dipankar
authors.initials: D
authors.lastname: Bhandari
authors.forename: Tobias
authors.initials: T
authors.lastname: Raisch
authors.forename: Oliver
authors.initials: O
authors.lastname: Weichenrieder
authors.forename: Stefanie
authors.initials: S
authors.lastname: Jonas
authors.forename: Elisa
authors.initials: E
authors.lastname: Izaurralde
mesh_terms: D020816:Amino Acid Motifs; D017124:Conserved Sequence; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006801:Humans; D008958:Models, Molecular; D046912:Multiprotein Complexes / Q000737:chemistry; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2 / Q000737:chemistry* / Q000378:metabolism*; D010455:Peptides / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D020836:Protein Structure, Quaternary; D020871:RNA Stability / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D054398:Receptors, CCR4 / Q000737:chemistry* / Q000378:metabolism*; D015203:Reproducibility of Results
chemical_list: C515354:CCR4 protein, human; D046912:Multiprotein Complexes; C539882:NR4A2 protein, human; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2; D010455:Peptides; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D054398:Receptors, CCR4
keywords: SLiM; deadenylation; decapping; mRNA decay; translational repression
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