Recent advances in MeCP2 structure and function - PubMed (original) (raw)

Review

Recent advances in MeCP2 structure and function

Kristopher C Hite et al. Biochem Cell Biol. 2009 Feb.

Abstract

Mutations in methyl DNA binding protein 2 (MeCP2) cause the neurodevelopmental disorder Rett syndrome (RTT). The mechanism(s) by which the native MeCP2 protein operates in the cell are not well understood. Historically, MeCP2 has been characterized as a proximal gene silencer with 2 functional domains: a methyl DNA binding domain and a transcription repression domain. However, several lines of new data indicate that MeCP2 structure and function relationships are more complex. In this review, we first discuss recent studies that have advanced understanding of the basic structural biochemistry of MeCP2. This is followed by an analysis of cell-based experiments suggesting MeCP2 is a regulator, rather than a strict silencer, of transcription. The new data establish MeCP2 as a multifunctional nuclear protein, with potentially important roles in chromatin architecture, regulation of RNA splicing, and active transcription. We conclude by discussing clinical correlations between domain-specific mutations and RTT pathology to stress that all structural domains of MeCP2 are required to properly mediate cellular function of the intact protein.

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Figures

Fig. 1

Fig. 1

Chronological representation of known MeCP2 functions. The progression of traditional understanding of MeCP2 as a methyl-dependent proximal gene silencer is shown in grey on the left, while studies implicating MeCP2 as having additional functions are listed on the right. CTD, carboxyl terminal domain.

Fig. 2

Fig. 2

Diagram of MeCP2 domain organization, based on biochemical data aligned with a FoldIndex plot. Domains are labeled from amino to carboxyl terminal from left to right. The location and sequence of the alternatively spliced region of the e1 and e2 isoforms is shown at the left. The boundaries of trypsin-resistant bands are indicated by black diamonds. The full-length protein sequence was analyzed by the FoldIndex algorithm (

http://bioportal.weizmann.ac.il/fldbin/findex

), with a window setting of 10 and a step value of 1. Regions that are predicted to be disordered are indicated in black, while ordered regions are shown in gray. Note that under these settings, the first and last 10 amino acids are not represented in the plot.

Fig. 3

Fig. 3

Schematic depicting MeCP2 with contingent domains labeled. Two common Rett syndrome (RTT) truncation mutations (R168X and R294X) and an RTT point mutation (R306C) are indicated along the peptide. The phenotypic pathology or combinations are correlated to each mutation with symbols.

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