FC0043
Methyl CpG binding protein 2 (MeCP2)  -  DNA

Biological function
MeCP2 reads epigenetic information encoded in DNA methylation patterns. MeCP2 has several autonomous DNA binding domains intercalated between ID regions, and mutations within these regions are associated with Rett syndrome.

Domain organization/sequence features
MeCP2 has two well defined functional domains. Residues 78–162 are required to specifically recognize methylated CpG dinucleotides and have been termed the methyl DNA binding domain (MBD). The minimal sequence needed to repress transfected DNA has been called the transcriptional repression domain (TRD) and consists of residues 207–310.

Structural evidence
The propensity of regular secondary structures is 35% in the free MeCP2, which increases only by 7% upon interacting with DNA. This indicates that although some secondary structure elements are distinguished in binding, MeCP2 remains primarily disordered in the complex. The secondary structure content of the disordered N-terminal domain (NTD), for example, exhibits almost no change in the effect of DNA, yet it impacts affinity of the structured MBD by 10-fold.

Biochemical evidence
Fusing the structured methylated DNA binding domain (MBD) with the disordered N-terminal domain (NTD) decreases the K_D for DNA from 8.5 nM to 0.8 nM.

Structure/Mechanism
The NTD does not harbor a DNA binding site; instead, through interdomain interactions, it populates those MBD conformations that favor DNA interactions. The NTD destabilizes the overall MBD structure, but the stability of the MBD–DNA and MBD– transcriptional regulatory domain (TRD)–DNA complexes are comparable. Hence, the ID region frustrates the native fold of the structured MBD domain, which is relieved by DNA interactions and improves binding affinity. Although its mechanism is far from being understood, fusion of the disordered MeCP2 C-terminal domain (CTD) to the TRD also increases binding affinity by 30-fold, even though the CTD does not adopt a well-defined structure in the complex.

Mechanism category
conformational selection

Isoforms, context-dependence
Alternative translation start sites in murine MeCP2 increase the length and flexibility of the disordered NTD. Given the role of the NTD in modulating the recognition of methylated CpG islands by transient interactions with the MBD, the different isoforms result in different gene expression patterns in mouse brain.

Significance
Fuzzy regions shift MBD conformations biased for DNA binding. In addition, they likely mediate interdomain contacts via embedded short motifs.

Medical relevance
Involvement in Rett syndrome (RTT), an X chromosome-linked neurodevelopmental disorder that afflicts one in 10,000–15,000 girls.

Submitted by
Jeffrey C Hansen   jchansen@lamar.colostate.edu