5NAF

Co-crystal structure of an MeCP2 peptide with TBLR1 WD40 domain

Summary for 5NAF

• Entry DOI: 10.2210/pdb5naf/pdb
• Descriptor: F-box-like/WD repeat-containing protein TBL1XR1, Methyl-CpG-binding protein 2, GLYCEROL, ... (4 entities in total)
• Functional Keywords: wd40 domain ; protein-peptide complex; transcriptional repressor; rett syndrome, transcription
• Biological source: Mus musculus (Mouse); More
• Cellular location: Nucleus : Q8BHJ5 Q9Z2D6
• Total number of polymer chains: 6
• Total formula weight: 183227.82

Authors

Kruusvee, V.,Cook, A.G. (deposition date: 2017-02-27, release date: 2017-03-29, Last modification date: 2024-11-13)

Primary citation

Kruusvee, V.,Lyst, M.J.,Taylor, C.,Tarnauskaite, Z.,Bird, A.P.,Cook, A.G.
Structure of the MeCP2-TBLR1 complex reveals a molecular basis for Rett syndrome and related disorders.
Proc. Natl. Acad. Sci. U.S.A., 114:E3243-E3250, 2017

PubMed Abstract: Rett syndrome (RTT) is an X-linked neurological disorder caused by mutations in the methyl-CpG-binding protein 2 () 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.

PubMed: 28348241
DOI: 10.1073/pnas.1700731114

Experimental method

X-RAY DIFFRACTION (2.493 Å)