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

Rett syndrome (RTT) is an X-linked neurological disorder caused by mutations in the MECP2 gene. The majority of RTT missense mutations disrupt the interaction of MeCP2 with DNA or the NCoR/SMRT co-repressor complex. Here we show that the “NCoR/SMRT Interaction Domain” (NID) of MeCP2 directly contacts TBL1 and TBLR1, two paralogues that are core components of NCoR/SMRT. We determine the co-crystal 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 that make 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.