P152R Mutation Within MeCP2 Can Cause Loss of DNA-Binding Selectivity

被引:0
作者
Dino Franklin
机构
[1] Federal University of Uberlandia,Faculty of Computing
来源
Interdisciplinary Sciences: Computational Life Sciences | 2019年 / 11卷
关键词
MeCP2; Rett syndrome; DNA-binding; Molecular dynamics;
D O I
暂无
中图分类号
学科分类号
摘要
MeCP2 is a protein highly expressed in the brain that participates in the genetic expression and RNA splicing regulation. MeCP2 binds preferably to methylated DNA and other nuclear corepressors to alter chromatin. MECP2 gene mutations can cause rett syndrome (RTT), a severe neurological disorder that affects around one in ten thousand girls. In this paper, Molecular Dynamics (MD) simulations were performed to scrutinize how the MeCP2 P152R mutation influences the protein binding to DNA. Also, the Umbrella Sampling technique was used to obtain the potential mean forces (PMFs) of both wild-type and mutated MeCP2 Methyl-CpG-binding domain (MBD) binding to both non-methylated and methylated DNA. P152R is a common missense mutation in MBD associated with RTT; however, there are no studies that explain how it causes protein dysfunction. The results from this study hypothesize that P152R mutation leads to MBD binding more strongly to DNA, while selectively decreasing binding affinity to methylated DNA. These provide an explanation for previous not conclusive experimental results regarding the mechanism of how this mutation affects the binding of the protein to DNA, and subsequently its effects on RTT. Furthermore, the results of this research-in-progress can be used as the basis for further investigations into the molecular basis of RTT and to potentially reveal a target for therapy in the future.
引用
收藏
页码:10 / 20
页数:10
相关论文
共 169 条
  • [1] Dragich J(2000)Rett syndrome: a surprising result of mutation in MECP2 Hum Mol Genet 9 2365-2375
  • [2] Houwink-Manville I(2006)The molecular pathology of Rett syndrome: synopsis and update Neuromol Med 8 485-494
  • [3] Schanen C(2007)Reversal of neurological defects in a mouse model of Rett syndrome Science 315 1143-1147
  • [4] Akbarian S(2008)Specific mutations in methyl-CpG-binding protein 2 confer different severity in Rett syndrome Neurology 70 1313-1321
  • [5] Jiang Y(1999)Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2 Nat Genet 23 185-188
  • [6] Laforet G(2004)Rett syndrome: a prototypical neurodevelopmental disorder Neuroscientist 10 118-128
  • [7] Guy J(2003)RettBASE: the IRSA MECP2 variation database—a new mutation database in evolution Hum Mutat 21 466-472
  • [8] Gan J(2003)Heterogeneity in residual function of MeCP2 carrying missense mutations in the methyl CpG binding domain J Med Genet 40 487-493
  • [9] Selfridge J(2010)Neuronal MeCP2 is expressed at near histone-octamer levels and globally alters the chromatin state Mol Cell 37 457-468
  • [10] Cobb S(2004)Mild overexpression of MeCP2 causes a progressive neurological disorder in mice Hum Mol Genet 13 2679-2689