Journal Article

Structure of the MeCP2–TBLR1 complex reveals a molecular basis for Rett syndrome and related disorders

Lyst, Matthew J., Tarnauskaitė, Žygimantė, Cook, Atlanta G., Taylor, Ceitidh, Kruusvee, Valdeko, Bird, Adrian P.

2017

Overview

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.

• Publisher: National Academy of Sciences
• Subject: Binding sites / Biochemistry / Biological Sciences / Brain / CpG islands / Crystallography, X-Ray / Deoxyribonucleic acid / Disorders / DNA / Genes / HeLa Cells / Humans / In vitro methods and tests / MeCP2 protein / Methyl-CpG binding protein / Methyl-CpG-Binding Protein 2 - chemistry / Methyl-CpG-Binding Protein 2 - genetics / Methyl-CpG-Binding Protein 2 - metabolism / Missense mutation / Molecules / Mutation / Mutation, Missense / Neurological disorders / Nuclear Proteins - chemistry / Nuclear Proteins - genetics / Nuclear Proteins - metabolism / Nuclear Receptor Co-Repressor 1 - chemistry / Nuclear Receptor Co-Repressor 1 - genetics / Nuclear Receptor Co-Repressor 1 - metabolism / PNAS Plus / Protein Conformation / Proteins / Receptors / Receptors, Cytoplasmic and Nuclear - chemistry / Receptors, Cytoplasmic and Nuclear - genetics / Receptors, Cytoplasmic and Nuclear - metabolism / Repressor Proteins - chemistry / Repressor Proteins - genetics / Repressor Proteins - metabolism / Residues / Retinoic acid / Rett syndrome / Rett Syndrome - genetics / Rett Syndrome - pathology / SMRT protein / Thyroid / Transducin / Transducin - chemistry / Transducin - genetics / Transducin - metabolism