Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.663340
Title: The solution structure and DNA interactions of the methyl-CpG binding domain of the protein, MeCP2, using NMR spectroscopy
Author: Wakefield, Robert I. D.
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2001
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Abstract:
DNA methylation and its associated histone deacetylation and chromatin modification are global mechanisms that regulate gene expression. MeCP2 is an abundant mammalian protein that specifically binds the 5-methyl-CpG (mCpG) dinucleotide pair, represses transcription by recruiting histone deacetylases, and is essential for embryonic development. Mutations in the McCP2 gene, which encodes the X-linked MeCP2 protein, have been identified as the cause of the progressive, neurodevelopment disorder, Rett syndrome (RTT, MIM312750). MeCP2 contains a methyl-CpG binding domain (MBD) and a transcriptional repression domain (TRD). The structure of MBD OF MeCP2 has been solved and is found to adopt a novel fold forming a wedge shape. It consists of a four-stranded antiparellel β-sheet, which forms one face of the wedge shape, a 3 turn α-helix and a single turn α-helix, which form the other face of the wedge. A long flexible loop between strands B and C (BC loop) forms the thin edge of the wedge and becomes structured upon binding to DNA. The BC loop together with residues in strands B, C and D, and at the N-terminus of the larger α-helix, appear to form an interface with methylated DNA. The guanidyl sidechains of Arg 111 and Arg 133 are also found to become structured upon binding to DNA and their mutation was found to inhibit binding. Thus they are believed to make direct contacts with DNA. The absence of symmetry in the domain implies that recognition does not exploit the symmetry of the binding site.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.663340  DOI: Not available
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