Rett Syndrome Protein

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Rett Syndrome Protein

Human MeCP2 MBD domain complex with DNA and CMP derivative (PDB code 3c2l)

Overview

The , also known as MeCP2, has a critical role in gene silencing. This mutation targets X-linked genes which are specific for cortical neurons. This effects neuronal maturity and plasticity resulting in poor neurological function. This protein is primarily responsible for the mutations in Rett Syndrome. The structure of this molecule was recently discovered which lead to a number of advancement for Rett Syndrome. MeCP2 protein binds in a hydrophobic pocket on the methylated BDNF DNA sequence. It then causes transcriptional repression through interaction with histone deacetylase and the corepressor SIN3A. [1] [2]


Function

The human MeCP2 is located on chromosome X, position 154,021,573-154,137,103. The primary role of MeCP2 protein is to aid in regulation of gene expression by modifying chromatin. This is primarily done in DNA methylation and histone acetylation during postnatal development. During DNA methylation MeCP2 protein directly interferes with the addition of a bulky methyl group during binding. The other method, histone acetylation, is more complex. MeCP2 indirectly prevents the methylation of a promotor region. Therefore the transcription protein is unable to identify the promotor region un-methylated inhibiting gene transcription. The MeCP2 protein is mainly located in the brain as it plays a major role in the function of neurons especially their synaptic transmission in the central nervous system. MeCP2 causes a significant decreased in spontaneous excitatory synaptic transmission. This causes an extreme shift in the ratio of inhibition to excitation. MeCP2 may also be involved in regulating mRNA by rearranging the molecules and inhibiting gene expression. Overall, this will limit learning and memory by effecting the hippocampus. Overall, it is important to note the number of systems MeCP2 protein participates in. Therefore, causing MeCP2 extremely difficult to treat if mutated. [3] [4] [5] [6]

History

In 1992, Lewis isolated MeCP2 protein from rat brain tissue. All that was known was that the MeCP2 protein specifically bound to methylated DNA due to its methyl binding domain. After a number of experiments it was confirmed MeCP2 protein will only bind to methylated DNA. At this time methylated DNA was believed to silence transcription due to the alteration of chromatin structure and condensing nucleosome display. Therefore the first correlation that MeCP2 is involved in gene expression arose. MeCP2 gene was originally believed to have three exon genes. With further studies it was realized there is another upstream non-coding exon. The original figure of MeCP2 contained exons 2, 3, and 4. However, with new research it was discovered that there are variant of MeCP2 which do not express exon 2. This group became classified as MeCP2B compared to the original three exon figure called MeCP2A. This new finding provided a significant amount of further understanding of the MeCP2 protein and its function. It was discovered that MeCP2B was dominate over MeCP2A although almost all scientific studies had been focused around MeCP2A.7 Therefore, the function had to be further investigated due to MeCP2B’s addition of an N-terminus that MeCP2A lacks. [6] [7]

Structure

The MeCP2 DNA Binding Domain binds to methylated BDNF DNA sequence primarily using hydrophobic pockets. It is able to recognize mCpG DNA by noticing 5 unique CH-O hydrogen bonds within water molecules. An example is how water-24 forms hydrogen bonds with Try 123, Arg 133, water 22, and m5C8. Compared to water-22 which forms hydrogen bonds with , waster-24, water-21, and N4 of m5C33. Only Asp 121 direct interacts with the DNA bases. It forms hydrogen bonds with methyl groups with Arg which are stabilized with salt bridges. The entire strand is comprised of 51% β-sheet, 10% α-helix, and almost 40% unstructured. The terminal carbon region contains a rare tandem ASX-ST motif which includes an proceeded by an . This unique turn is stabilized with hydrogen bond interactions connecting the nitrogens between amino acids. These finds are consistent as typically MeCP2 behaves as a monomer while in ionic conditions and molar concentrations, and had an unusually low sedimentation coefficient (2.2 S) and a correspondingly high frictional coefficient ratio (f/fo = 2.4). This proves the helical structure. MeCP2 is comprised of six biochemically distinct domains which are located at the N-terminus. It includes HMGD1, MBD, HMGD2, TRD, carboxyl terminal domain (CTD)-α, and CTD-β from the amino to carboxyl terminals. Some of these site are rapidly digested by Trypsin while others are restricted. The two more important for the protein’s function include MBD which is selectively binds 5MeCyt and the other is TRD which binds cofactors attracting histone deacetylase and leads to transcription repression. In addition, MBD is the only structured domain. The MBD domain contains the most common missense mutation causing Rett Syndrome when there is a change in the ASX-ST motif. This minor alteration inhibits the binding of DNA. This topic will be further discussed later in the literature. [2] [8] [7]

Reactions and Mechanism

The activation mechanism is explained as follows: MECP2 recruits CREB1 as a cofactor to target gene promotors. MECP2 binding to 5OHMeCyt was even interpreted as a marker of active genes in neurons. MECP2 was also found to form a TET1 containing complex which leads to 5MeCyt hydroxylation and further to demethylation of DNA, enabling transcription. This mechanism was found to activate expression of downstream genes. [7]

Regulation

There are several cis- and trans-regulatory elements for MECP2 gene expression regulation known. Cis regulatory elements, include promotor elements while trans-elements affect the regulation in an indirect way and can be located close or far away to the binding site. Translation of MECP2 can be regulated by a set of microRNAs which are small non-coding RNAs which repress translation mRNA into protein. In addition, MeCP2 undergoes a number of post translational modifications including phosphorylation, acetylation, SUMOylation, and ubiquitination. [7]

Kinetics

The effect of demethylation on MeCP2 binding kinetics is therefore underestimated. When MeCP2 is decreased from pericentromeric heterochromatin (PHC) upon the blocking of DNA methylation is combined with the accelerated chromatin binding kinetics it demonstrates that stereospecific binding to methyl-CpG accounts for the increased residence time of MeCP2 in PHC and also for the fraction tightly bound to chromatin. In general, the Fluorescence photobleaching (FRAP) kinetics of wild-type MeCP2 are much faster than the core histone components, but close to the kinetics of the linker histone H1. [9] [10]

Medical Implications: Rett Syndrome

Rett Syndrome is a gradual neurodevelopmental disorder effected 1 in 10,000 to 15,000 females. Patients with Rett Syndrome typically develop normally until around 6 to 8 months of age. At this time the patient begins to go through a period of regression losing previously acquired skills. After this period of regression, most patients are able to become stable and survive into mid-adulthood. As many other disorders are, MeCP2 is an X linked dominant trait. A mutation within this protein is the most common cause of Rett Syndrome. Therefore, females that are heterozygous are able to survive with the mutation within MeCP2 due to X inactivation. Males on the other hand, are typically unable to survive, or have severely shortened lifespan. The mutation that occurs within the MeCP2 protein could be a missense, nonsense, insertion, deletion, or any other genetic change within the gene or protein. T158M, which is the most common missense mutation causing Rett Syndrome by abolishing DNA binding because it disrupts this ASX-ST motif. Another well-known Rett inducing mutation, R106W, disrupts the ASX-ST motif by stabilizing hydrogen bonds between Arg 106 and Thr 158 and Val 159. These errors in MeCP2 result in loss of purposeful hand movements, slowed brain and head growth, gait abnormalities, and mental retardation. In addition, most Rett syndrome patients experience seizures, breathing irregularities, scoliosis, and an abnormal cardiac cycle. The primary locations which mutations causing the major symptoms in Rett Syndrome are: . Most of these mutation all occur within the MBD region of MeCP2.3 [11] [5] [2]

References

  1. Hagberg, B. Rett's syndrome: prevalence and impact on progressive severe mental retardation in girls. Acta Paediatr. Scand. 74, 405– 408 (1985).https://www.nature.com/articles/ng1099_185 Accessed March 7, 2019
  2. 2.0 2.1 2.2 Marchetto M, Carromeu C, Acab A, et al. A Model for Neural Development and Treatment of Rett Syndrome Using Human Induced Pluripotent Stem Cells. Science Direct . https://www.sciencedirect.com/science/article/pii/S0092867410011864?via=ihub. Published November 12, 2010. Accessed March 10, 2019.
  3. Ehrhart F, Coort SLM, Cirillo E, Smeets E, Evelo CT, Curfs LMG. Rett syndrome - biological pathways leading from MECP2 to disorder phenotypes. Orphanet journal of rare diseases. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5123333/. Published November 25, 2016. Accessed March 10, 2019.
  4. MECP2 gene - Genetics Home Reference - NIH. U.S. National Library of Medicine. https://ghr.nlm.nih.gov/gene/MECP2. Published March 2017. Accessed March 10, 2019.
  5. 5.0 5.1 Na ES, Monteggia LM. The role of MeCP2 in CNS development and function. Hormones and behavior. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3077534/. Published March 2011. Accessed March 20, 2019.
  6. 6.0 6.1 Webb T, Latif F. Rett Syndrome and the MECP2 gene. https://jmg.bmj.com/content/jmedgenet/38/4/217.full.pdf. Published April 2001. Accessed March 7, 2019.
  7. 7.0 7.1 7.2 7.3 Warby S. Discovery of a new protein isoform of MeCP2 and exon 1 mutations causing Rett syndrome. HotSpots.:108-110. https://maryville.illiad.oclc.org/illiad/pdf/157498.pdf. Accessed March 7, 2019.
  8. Hite KC, Adams VH, Hansen JC. Recent advances in MeCP2 structure and function. Biochemistry and cell biology = Biochimie et biologie cellulaire. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2874317/. Published February 2009. Accessed March 7, 2019.
  9. Ghosh RP, Horowitz-Scherer RA, Nikitina T, Shlyakhtenko LS, Woodcock CL. MeCP2 Binds Cooperatively to Its Substrate and Competes with Histone H1 for Chromatin Binding Sites. Molecular and Cellular Biology. https://mcb.asm.org/content/30/19/4656. Published October 1, 2010. Accessed March 10, 2019.
  10. Agarwal N, Becker A, Jost L, et al. MeCP2 Rett mutations affect large scale chromatin organization. OUP Academic. https://academic.oup.com/hmg/article/20/21/4187/577248. Published August 10, 2011. Accessed March 8, 2019.
  11. Amir RE, Van den Veyver IB, Wan M, Tran CQ, Francke U, Zoghbi HY. Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2. Nature genetics. https://www.ncbi.nlm.nih.gov/pubmed/10508514/. Published October 1999. Accessed March 8, 2019.

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