Methyl CpG Binding Protein 2

Methyl CpG Binding Protein 2 (MeCP2) is a transcriptional repressor that plays a critical gene silencing role. It binds the methylated BDNF DNA sequence with exquisite specificity and recruits repressor complexes which include chromatin-remodeling enzymes.^[1] MeCP2, encoded by an X-linked gene, has been found in most tissues but is primarily localized to cortical neurons where it is believed to help modulate neuronal maturity and plasticity.^[2] It also plays a crucial role in synaptogenesis and in maintaining proper neuronal function.^[1] Of particular note, mutations within the MeCP2 gene are responsible for over 95% of cases of Rett Syndrome. Rett Syndrome (RTT) is an autism spectrum neurodevelopmental disorder caused by the expression of mutant MeCP2 . RTT patients present with abnormal neuronal morphology and have a large spectrum of autistic characteristics such as impaired motor function and impaired developmental skills. These symptoms become first evident 6-18 months after birth.^[3] Intriguingly, Guy et al. demonstrated that the restoration of neuronal function by knock-in expression of MeCP2 in mice can reverse many of the RTT phenotypic traits.^[4]

Structure of MeCP2

     The crystal structure of the DNA binding domain of MeCP2 was solved by Ho et al. in 2008 providing researchers with critical new information about the cause of RTT at the molecular level. binds the using a predominantly . MeCP2 recognition of the mCpG DNA sequence involves each making unique CH-O hydrogen bonds. with Asp 121, water-24, water-21, and N4 of m5C33. with Tyr 123, Arg 133, water 22, as well as m5C8 and a CH-O hydrogen bond interaction with the methyl group of m5C8. The only residues that directly interact with DNA bases , which forms hydrogen bond with the methyl group of m5C8, and , each of which form hydrogen bonds with a guanine DNA base. Both of these “Arginine Fingers” and are secured into this position by . These interactions place the gaunidines directly of the methyl-cytidines.^[1] The C-terminal region of includes an unusual . This motif consists of an ASX turn (Residues 156-158) directly followed by an ST motif (158-161). The by a hydrogen bond interaction connecting the nitrogen of Thr 158 and Asp 156. The by hydrogen bonds to Thr 158. T158M, which is the most common missense mutation causing Rett Syndrome abolishes DNA binding because it disrupts this ASX-ST motif. Another well-known RTT inducing mutation, R106W, disrupts the ASX-ST motif stabilizing hydrogen bonds between . This ASX-ST motif stabilizes MeCP2’s interaction with DNA by specifically binding to the which is 3 angstroms narrower than a typical DNA minor groove, due to the consecutive A/T bases. This unique trait helps account for MeCP2’s exquisite precision.^[1]

     Overall, the solved crystal structure of the MBD of MeCP2 reveals why certain known mutations are so deleterious as to cause Rett Syndrome and hopefully elucidates potential avenues for pharmaceutical intervention. See also Neurodevelopmental Disorders.