title: The molecular basis for ANE syndrome revealed by the large ribosomal subunit processome interactome.
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 one aspect of the molecular basis of this human disease.
authors.affiliation: Department of Genetics, Yale University School of Medicine, New Haven, United States.
authors.forename: Kathleen L
authors.identifier: 0000-0002-7144-4851
authors.initials: KL
authors.lastname: McCann
authors.affiliation: Epigenetics and Stem Cell Biology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, United States.
authors.forename: Takamasa
authors.initials: T
authors.lastname: Teramoto
authors.affiliation: Epigenetics and Stem Cell Biology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, United States.
authors.forename: Jun
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Epigenetics and Stem Cell Biology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, United States.
authors.forename: Traci M
authors.initials: TM
authors.lastname: Tanaka Hall
authors.affiliation: Department of Genetics, Yale University School of Medicine, New Haven, United States.|Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, United States.|Department of Molecular Biophysics and Biochemistry, Yale University School of Medicine, New Haven, United States.
authors.forename: Susan J
authors.initials: SJ
authors.lastname: Baserga
mesh_terms: D000505:Alopecia / Q000503:physiopathology*; D002942:Circular Dichroism; D004700:Endocrine System Diseases / Q000503:physiopathology*; D006801:Humans; D008607:Intellectual Disability / Q000503:physiopathology*; D009682:Magnetic Resonance Spectroscopy; D008954:Models, Biological; D050505:Mutant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D017510:Protein Folding; D060066:Protein Interaction Maps; D012322:RNA Precursors / Q000378:metabolism; D012323:RNA Processing, Post-Transcriptional; D016601:RNA-Binding Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D020718:Ribonucleoproteins, Small Nucleolar / Q000235:genetics / Q000378:metabolism*; D054658:Ribosome Subunits, Large / Q000378:metabolism*; D012441:Saccharomyces cerevisiae / Q000235:genetics* / Q000254:growth & development / Q000378:metabolism / Q000502:physiology*; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D050505:Mutant Proteins; C088476:NOP4 protein, S cerevisiae; C530063:RBM28 protein, human; D012322:RNA Precursors; D016601:RNA-Binding Proteins; D020718:Ribonucleoproteins, Small Nucleolar; D029701:Saccharomyces cerevisiae Proteins
keywords: ANE syndrome; Nop4; RNA recognition motif; S. cerevisiae; biophysics; chromosomes; genes; human; ribosome biogenesis; structural biology