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          Institute: MPI für Entwicklungsbiologie     Collection: Abteilung 2 - Biochemistry (E. Izaurralde)     Display Documents

ID: 708194.0, MPI für Entwicklungsbiologie / Abteilung 2 - Biochemistry (E. Izaurralde)
Structural basis for the Nanos-mediated recruitment of the CCR4-NOT complex and translational repression
Authors:Bhandari, D.; Raisch, T.; Weichenrieder, O.; Jonas, S.; Izaurralde, E.
Date of Publication (YYYY-MM-DD):2014-04-15
Title of Journal:Genes & Development
Journal Abbrev.:Genes Dev
Issue / Number:8
Start Page:888
End Page:901
Sequence Number of Article:24736845
Review Status:Internal review
Audience:Experts Only
Abstract / Description: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.
Free Keywords:Amino Acid Motifs; Conserved Sequence; *Gene Expression Regulation; HEK293 Cells; Humans; *Models, Molecular; Multiprotein Complexes/chemistry; Nuclear Receptor Subfamily 4, Group A, Member 2/*chemistry/*metabolism; Peptides/chemistry/metabolism; Protein Binding; Protein Structure, Quaternary; RNA Stability/genetics; RNA, Messenger/metabolism; RNA-Binding Proteins/genetics/*metabolism; Receptors, CCR4/*chemistry/*metabolism; Reproducibility of Results
External Publication Status:published
Document Type:Article
Communicated by:root
Affiliations:MPI für Entwicklungsbiologie/Abteilung 2 - Biochemie (Elisa Izaurralde)
Identifiers:ISSN:1549-5477 (Electronic) 0890-9369 (Linking) %R 10.1... [ID No:1]
URL:http://www.ncbi.nlm.nih.gov/pubmed/24736845 [ID No:2]
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