Methyl CpG Binding Protein 2

From Proteopedia

References

1. ↑ ^{1.0 1.1} Ho KL, McNae IW, Schmiedeberg L, Klose RJ, Bird AP, Walkinshaw MD. MeCP2 binding to DNA depends upon hydration at methyl-CpG. Mol Cell. 2008 Feb 29;29(4):525-31. PMID:18313390 doi:10.1016/j.molcel.2007.12.028
2. ↑ Zoghbi HY. Postnatal neurodevelopmental disorders: meeting at the synapse? Science. 2003 Oct 31;302(5646):826-30. PMID:14593168 doi:10.1126/science.1089071
3. ↑ Marchetto MC, Carromeu C, Acab A, Yu D, Yeo GW, Mu Y, Chen G, Gage FH, Muotri AR. A model for neural development and treatment of Rett syndrome using human induced pluripotent stem cells. Cell. 2010 Nov 12;143(4):527-39. PMID:21074045 doi:10.1016/j.cell.2010.10.016
4. ↑ PMID:17289941/<ref> &nbsp;&nbsp;&nbsp;&nbsp;&nbsp;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. **The MeCP2 DNA Binding Domain (MBD) ** binds the **methylated BDNF DNA sequence** using a predominantly hydrophilic pocket. MeCP2 recognition of the mCpG sequence involves **five water molecules** each making CH-O hydrogen bonds. **W22 forms hydrogen bonds** with Asp 121, W24, W21, and N4 of m5C33. **W22 forms hydrogen bonds** with Tyr 123, Arg 133, water 22, and both N4 of m5C8 and a CH-O interaction with the methyl group of m5C8. The only residues that directly interact with DNA bases are **Asp 121**, forming a CH-O hydrogen bond with methyl of m5C8, **Arg 111, and Arg 133**, each of which form symmetrical hydrogen bonds with each quinine in the mCpG pair. Both of these “Arginine Fingers”** lie in a plane with the guanine bases** and are locked into position by **salt bridges with Asp 121 and Glu 137**, placing the gaunidinum groups directly above/below the methyl groups of the methylated cytidine bases.<ref name="Bird"/> The C-terminal region of the MBD includes an unusual **tandem Asx-ST motif**, that consists of an Asx turn (Residues 156-158) followed by an ST motif (158-161). The **Asx turn is formed** by a hydrogen bond that connects the main chain nitrogen of Thr 158 and the side chain of Asp 156, while the ST motif is held together 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 mutation, causing RTT, R106W, disrupts the motif stabilizing hydrogen bonds formed between **Arg 106 and Thr 158 and Val 159**. This Asx-ST motif stabilizes MeCP2’s interaction with DNA by specifically binding to the **AATT minor groove** which has a nearly 3 angstrom narrower interphosphate distance than a typical minor groove, due to the consecutive A/T bases. This unique trait helps account for MeCP2’s exquisite precision.<ref name="Bird"/> &nbsp;&nbsp;&nbsp;&nbsp;&nbsp;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. __NOEDITSECTION__ __NOTOC__ </li></ol></ref>