title: Structure of the MeCP2-TBLR1 complex reveals a molecular basis for Rett syndrome and related disorders.
abstract: Rett syndrome (RTT) is an X-linked neurological disorder caused by mutations in the methyl-CpG-binding protein 2 (MeCP2) gene. The majority of RTT missense mutations disrupt the interaction of the MeCP2 with DNA or the nuclear receptor corepressor (NCoR)/silencing mediator of retinoic acid and thyroid receptors (SMRT) corepressor complex. Here, we show that the "NCoR/SMRT interaction domain" (NID) of MeCP2 directly contacts transducin beta-like 1 (TBL1) and TBL1 related (TBLR1), two paralogs that are core components of NCoR/SMRT. We determine the cocrystal structure of the MeCP2 NID in complex with the WD40 domain of TBLR1 and confirm by in vitro and ex vivo assays that mutation of interacting residues of TBLR1 and TBL1 disrupts binding to MeCP2. Strikingly, the four MeCP2-NID residues mutated in RTT are those residues that make the most extensive contacts with TBLR1. Moreover, missense mutations in the gene for TBLR1 that are associated with intellectual disability also prevent MeCP2 binding. Our study therefore reveals the molecular basis of an interaction that is crucial for optimal brain function.
authors.affiliation: Wellcome Trust Centre for Cell Biology, University of Edinburgh, Edinburgh EH9 3BF, United Kingdom.
authors.forename: Valdeko
authors.initials: V
authors.lastname: Kruusvee
authors.affiliation: Wellcome Trust Centre for Cell Biology, University of Edinburgh, Edinburgh EH9 3BF, United Kingdom.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Lyst
authors.affiliation: Wellcome Trust Centre for Cell Biology, University of Edinburgh, Edinburgh EH9 3BF, United Kingdom.
authors.forename: Ceitidh
authors.initials: C
authors.lastname: Taylor
authors.affiliation: MRC Human Genetics Unit, MRC Institute of Genetics & Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh EH4 2XU, United Kingdom.
authors.forename: Žygimantė
authors.initials: Ž
authors.lastname: Tarnauskaitė
authors.affiliation: Wellcome Trust Centre for Cell Biology, University of Edinburgh, Edinburgh EH9 3BF, United Kingdom; a.bird@ed.ac.uk atlanta.cook@ed.ac.uk.
authors.forename: Adrian P
authors.initials: AP
authors.lastname: Bird
authors.affiliation: Wellcome Trust Centre for Cell Biology, University of Edinburgh, Edinburgh EH9 3BF, United Kingdom; a.bird@ed.ac.uk atlanta.cook@ed.ac.uk.
authors.forename: Atlanta G
authors.initials: AG
authors.lastname: Cook
mesh_terms: D018360:Crystallography, X-Ray; D006367:HeLa Cells; D006801:Humans; D051783:Methyl-CpG-Binding Protein 2 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D020125:Mutation, Missense; D009687:Nuclear Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D056971:Nuclear Receptor Co-Repressor 1 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D011487:Protein Conformation; D018160:Receptors, Cytoplasmic and Nuclear / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D015518:Rett Syndrome / Q000235:genetics* / Q000473:pathology; D015293:Transducin / Q000737:chemistry / Q000235:genetics / Q000378:metabolism
chemical_list: C497392:MECP2 protein, human; D051783:Methyl-CpG-Binding Protein 2; C539127:NCOR1 protein, human; D009687:Nuclear Proteins; D056971:Nuclear Receptor Co-Repressor 1; D018160:Receptors, Cytoplasmic and Nuclear; D012097:Repressor Proteins; C119542:TBL1X protein, human; C473691:TBL1XR1 protein, human; D015293:Transducin
keywords: MeCP2; NCoR/SMRT; Rett syndrome; TBL proteins; intellectual disability