1. Structural Biology and Molecular Biophysics
  2. Chromosomes and Gene Expression

The molecular basis for ANE syndrome revealed by the large ribosomal subunit processome interactome

  1. Kathleen McCann
  2. Takamasa Teramoto
  3. Jun Zhang
  4. Traci M Tanaka Hall
  5. Susan J Baserga  Is a corresponding author
  1. National Institute of Environmental Health Sciences, National Institutes of Health, United States
  2. Yale University, United States
https://doi.org/10.7554/eLife.16381
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  1. Kathleen McCann
  2. Takamasa Teramoto
  3. Jun Zhang
  4. Traci M Tanaka Hall
  5. Susan J Baserga
(2016)
The molecular basis for ANE syndrome revealed by the large ribosomal subunit processome interactome
eLife 5:e16381.
https://doi.org/10.7554/eLife.16381
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Abstract

ANE syndrome is a ribosomopathy caused by a mutation in an RNA recognition motif of RBM28, a nucleolar protein conserved to yeast (Nop4). While patients with ANE syndrome have fewer mature ribosomes, it is unclear how this mutation disrupts ribosome assembly. Here we use yeast as a model system and show that the mutation confers growth and pre-rRNA processing defects. Recently, we found that Nop4 is a hub protein in the nucleolar large subunit (LSU) processome interactome. Here we demonstrate that the ANE syndrome mutation disrupts Nop4's hub function by abrogating several of Nop4's protein-protein interactions. Circular dichroism and NMR demonstrate that the ANE syndrome mutation in RRM3 of human RBM28 disrupts domain folding. We conclude that the ANE syndrome mutation generates defective protein folding which abrogates protein-protein interactions and causes faulty pre-LSU rRNA processing, thus revealing the molecular basis of this human disease.

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Author details

  1. Kathleen McCann

    Epigenetics and Stem Cell Biology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, United States
    Competing interests
    The authors declare that no competing interests exist.

  2. Takamasa Teramoto

    Epigenetics and Stem Cell Biology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, United States
    Competing interests
    The authors declare that no competing interests exist.

  3. Jun Zhang

    Epigenetics and Stem Cell Biology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, United States
    Competing interests
    The authors declare that no competing interests exist.

  4. Traci M Tanaka Hall

    Epigenetics and Stem Cell Biology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, United States
    Competing interests
    The authors declare that no competing interests exist.

  5. Susan J Baserga

    Department of Genetics, Yale University, New Haven, United States
    For correspondence
    susan.baserga@yale.edu
    Competing interests
    The authors declare that no competing interests exist.

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This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.

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  1. Kathleen McCann
  2. Takamasa Teramoto
  3. Jun Zhang
  4. Traci M Tanaka Hall
  5. Susan J Baserga
(2016)
The molecular basis for ANE syndrome revealed by the large ribosomal subunit processome interactome
eLife 5:e16381.
https://doi.org/10.7554/eLife.16381

Share this article

https://doi.org/10.7554/eLife.16381

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    1. Developmental Biology
    2. Structural Biology and Molecular Biophysics

    A crystal structure of a collaborative RNA regulatory complex reveals mechanisms to refine target specificity

    Chen Qiu, Vandita D Bhat ... Traci M Tanaka Hall
    Research Advance Updated

    In the Caenorhabditis elegans germline, fem-3 Binding Factor (FBF) partners with LST-1 to maintain stem cells. A crystal structure of an FBF-2/LST-1/RNA complex revealed that FBF-2 recognizes a short RNA motif different from the characteristic 9-nt FBF binding element, and compact motif recognition coincided with curvature changes in the FBF-2 scaffold. Previously, we engineered FBF-2 to favor recognition of shorter RNA motifs without curvature change (Bhat et al., 2019). In vitro selection of RNAs bound by FBF-2 suggested sequence specificity in the central region of the compact element. This bias, reflected in the crystal structure, was validated in RNA-binding assays. FBF-2 has the intrinsic ability to bind to this shorter motif. LST-1 weakens FBF-2 binding affinity for short and long motifs, which may increase target selectivity. Our findings highlight the role of FBF scaffold flexibility in RNA recognition and suggest a new mechanism by which protein partners refine target site selection.