Activity-dependent phosphorylation of MeCP2 threonine 308 regulates interaction with NCoR

Ebert, Daniel H.; Gabel, Harrison W.; Robinson, Nathaniel D.; Kastan, Nathaniel; Hu, Linda; Cohen, Sonia; Navarro, Adrija J.; Lyst, Matthew J.; Ekiert, Robert; Bird, Adrian; Greenberg, Michael E.

doi:10.1038/nature12348

Cited by 206 publications

(176 citation statements)

References 26 publications

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“…S2A). TBL1 WD40 domain was efficiently pulled down by wild-type NID but not by RTT mutant peptides or a peptide containing phosphoThr308, a modification known to interfere with NID binding (24) (Fig. 2C).…”

Section: Mecp2mentioning

confidence: 99%

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

Kruusvee

Lyst

Taylor

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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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.T he methyl-CpG-binding protein 2 (MeCP2) is a chromatinassociated factor that is highly expressed in the brain (1, 2). Loss-of-function mutations in MeCP2 lead to the severe pediatric neurological disorder, Rett syndrome (RTT) (3), which affects around one in 10,000 girls. In addition, extra copies of the gene cause MeCP2 duplication syndrome (4, 5), a distinct intellectual disability disorder that predominantly affects males (6). The importance of MeCP2 for brain function has prompted investigation of its molecular function. The protein was identified because of its ability to bind DNA via its methyl-CpG-binding domain (MBD) (1, 7) and many residues mutated in RTT disrupt this interaction (8-11). In addition to DNA, numerous protein partners of MeCP2 have been reported (11). Of these protein partners, only the interactions with the nuclear receptor corepressor (NCoR) and its close relative silencing mediator of retinoic acid and thyroid receptors (SMRT) (12-14) are known to be disrupted by RTT missense mutations (13). Accordingly, Rett missense mutations outside the MBD are found clustered within the so-called "NCoR/SMRT interaction domain" (NID) (13) (Fig. 1A and Fig. S1A). One NID mutation, R306C, causes a severe RTT-like phenotype in mice (13,15,16). Moreover, mouse models of MeCP2 duplication syndrome suggest that both the MBD and the NID must be intact for this adverse molecular pathology to develop (16,17).These findings indicate that the NID mediates an essential function of MeCP2. This function may be recruitment of the NCoR/ SMRT corepressor complexes to chromatin. Alternatively, the NID may perform other essential roles, such as DNA binding, whose loss leads to RTT (16). In an attempt to distinguish among these possibilities, we investigated the molecular basis of the interaction between MeCP2 and NCoR/SMRT. The latter are ∼1.2-MDa multisubunit complexes that include NCoR1 (and/or SMRT), HDAC3, GPS2, and...

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Section: Mecp2mentioning

confidence: 99%

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

Kruusvee

Lyst

Taylor

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…85 MeCP2 function can be regulated by miRNAs 86,87 and activity dependent phosphorylation. 88,89 The significance of this to RTT is unclear however as there are no reports to date of RTT-causing point mutations within known MeCP2 phosphorylation sites. The level of MeCP2 within a given cell type is believed to be critical for normal cellular homeostasis and neurological consequences result from both loss of function and overexpression perturbations.…”

Section: Mecp2 Mutations and Protein Functionmentioning

confidence: 99%

Clinical and biological progress over 50 years in Rett syndrome

2016

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It is fifty years since Andreas Rett first described Rett syndrome, a disorder now known to be caused by a mutation in the MECP2 gene. A compelling blend of astute clinical observations, clinical and laboratory research has already built our understanding of Rett syndrome and its biological underpinnings. We document the contributions of the early pioneers and describe the evolution of knowledge in terms of diagnostic criteria, clinical variation and the interplay with other Rett-related disorders. We provide a synthesis of what is known about the neurobiology of MeCP2, the lessons from both cell and animal models and how they may inform future clinical trials. With a focus on the core criteria, we examine the relationships that have been demonstrated between genotype and clinical severity. We review what is known about the many comorbidities that occur in this disorder and how genotype may also modify their presentation. We acknowledge the important drivers that are accelerating this research program including the roles of research infrastructure, international collaboration and advocacy groups. Finally, we conclude by highlighting the major milestones since 1966 and what they mean for the day-to-day lives of those with Rett syndrome and their families. Key pointsThere has been an explosion of knowledge about Rett syndrome in relation to its genetic basis, clinical characteristics and their relationships during the fifty years since the disorder was first described by Andreas Rett.Whilst initially the diagnosis of Rett syndrome was based only on clinical criteria, identifying its genetic cause has had a major positive impact on how clinicians diagnose the disorder but also provides new challenges as we enter the era of next generation sequencing.

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“…Similarly, the discovery of a patient with a DN LGD mutation in NCOR1 (Table 3), now in addition to published DN missense mutations in ASD 12 and DD 28 cohorts, is exciting in light of the known interaction of the Rett syndrome gene (MECP2) with members of this nuclear receptor co-repressor complex 39,40 .…”

Section: Febrile Seizures Infancymentioning

confidence: 99%