MeCP2 is a methyl CpG binding protein whose key role is the recognition of epigenetic information encoded in DNA methylation patterns. Mutation or mis-regulation of MeCP2 function leads to Rett syndrome as well as a variety of other...
moreMeCP2 is a methyl CpG binding protein whose key role is the recognition of epigenetic information encoded in DNA methylation patterns. Mutation or mis-regulation of MeCP2 function leads to Rett syndrome as well as a variety of other Autism Spectrum Disorders. Here, we have analyzed in detail the properties of six individually expressed human MeCP2 domains spanning the entire protein with emphasis on their interactions with each other, with DNA, and with nucleosomal arrays. Each domain contributes uniquely to the structure and function of the full-length protein. MeCP2 is ~60% unstructured, with nine interspersed α-Molecular Recognition Features (α-MoRFs), which are polypeptide segments predicted to acquire secondary structure upon forming complexes with binding partners. Large increases in secondary structure content are induced in some of the isolated MeCP2 domains and in the full-length protein by binding to DNA. Interactions between some MeCP2 domains in cis and trans seen in our assays, likely contribute to the structure and function of the intact protein. We also show that MeCP2 has two functional halves. The N-terminal portion contains the methylated DNA binding domain (MBD) and two highly disordered flanking domains which modulate MBD-mediated DNA binding. One of these flanking domains is also capable of autonomous DNA binding. In contrast, the C-terminal portion of the protein which harbors at least two independent DNA binding domains and a chromatin specific binding domain is largely responsible for mediating nucleosomal array compaction and oligomerization. These findings lead to new mechanistic and biochemical insights regarding the conformational modulations of this intrinsically disordered protein, and its context-dependent in vivo roles. † Supported by NIH GM070897 and International Rett Syndrome Foundation (CLW); NIH GM066834 (JCH); NIH GM027616 and OD945 (LMG); NIH LM007688, GM071714, the program of the Russian Academy of Sciences for "Molecular and Cellular Biology", and the IUPUI Signatures Center Initiative (VNU).