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  1. Article ; Online: Coil-to-helix transitions in intrinsically disordered methyl CpG binding protein 2 and its isolated domains.

    Hite, Kristopher C / Kalashnikova, Anna A / Hansen, Jeffrey C

    Protein science : a publication of the Protein Society

    2012  Volume 21, Issue 4, Page(s) 531–538

    Abstract: ... terminal (NTD) and C-terminal (CTD) domains were partially converted to α-helix in 70% TFE. In contrast ...

    Abstract Methyl CpG binding protein 2 (MeCP2) is a canonical intrinsically disordered protein (IDP), that is, it lacks stable secondary structure throughout its entire polypeptide chain. Because IDPs often have the propensity to become locally ordered, we tested whether full-length MeCP2 and its constituent domains would gain secondary structure in 2,2,2-trifluoroethanol (TFE), a cosolvent that stabilizes intramolecular hydrogen bonding in proteins. The α-helix, β-strand/turn, and unstructured content were determined as a function of TFE concentration by deconvolution of circular dichroism data. Results indicate that approximately two-thirds of the unstructured residues present in full-length MeCP2 were converted to α-helix in 70% TFE without a change in β-strand/turn. Thus, much of the MeCP2 polypeptide chain undergoes coil-to-helix transitions under conditions that favor intrachain hydrogen bond formation. The unstructured residues of the N-terminal (NTD) and C-terminal (CTD) domains were partially converted to α-helix in 70% TFE. In contrast, the central transcription regulation domain (TRD) became almost completely α-helical in 70% TFE. Unlike the NTD, CTD, and TRD, the unstructured content of the methyl DNA binding domain and the intervening domain did not change with increasing TFE concentration. These results indicate that the coil-to-helix transitions that occur in full-length MeCP2 are localized to the NTD, CTD, and TRD, with the TRD showing the greatest tendency for helix formation. The potential relationships between intrinsic disorder, coil-to-helix transitions, and MeCP2 structure and function are discussed.
    MeSH term(s) Animals ; Chickens ; DNA-Binding Proteins/chemistry ; DNA-Binding Proteins/isolation & purification ; Dose-Response Relationship, Drug ; Histones/chemistry ; Humans ; Hydrogen Bonding ; Methyl-CpG-Binding Protein 2/chemistry ; Methyl-CpG-Binding Protein 2/isolation & purification ; Protein Folding ; Protein Stability ; Protein Structure, Secondary ; Protein Structure, Tertiary ; Solvents/chemistry ; Structure-Activity Relationship ; Trifluoroethanol/chemistry ; Trifluoroethanol/pharmacology
    Chemical Substances DNA-Binding Proteins ; Histones ; Methyl-CpG-Binding Protein 2 ; Solvents ; Trifluoroethanol (75-89-8)
    Language English
    Publishing date 2012-03-09
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 1106283-6
    ISSN 1469-896X ; 0961-8368
    ISSN (online) 1469-896X
    ISSN 0961-8368
    DOI 10.1002/pro.2037
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 3407: Show issues Location:
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  2. Article: Recent advances in MeCP2 structure and function.

    Hite, Kristopher C / Adams, Valerie H / Hansen, Jeffrey C

    Biochemistry and cell biology = Biochimie et biologie cellulaire

    2009  Volume 87, Issue 1, Page(s) 219–227

    Abstract: Mutations in methyl DNA binding protein 2 (MeCP2) cause the neurodevelopmental disorder Rett syndrome (RTT). The mechanism(s) by which the native MeCP2 protein operates in the cell are not well understood. Historically, MeCP2 has been characterized as a ... ...

    Abstract Mutations in methyl DNA binding protein 2 (MeCP2) cause the neurodevelopmental disorder Rett syndrome (RTT). The mechanism(s) by which the native MeCP2 protein operates in the cell are not well understood. Historically, MeCP2 has been characterized as a proximal gene silencer with 2 functional domains: a methyl DNA binding domain and a transcription repression domain. However, several lines of new data indicate that MeCP2 structure and function relationships are more complex. In this review, we first discuss recent studies that have advanced understanding of the basic structural biochemistry of MeCP2. This is followed by an analysis of cell-based experiments suggesting MeCP2 is a regulator, rather than a strict silencer, of transcription. The new data establish MeCP2 as a multifunctional nuclear protein, with potentially important roles in chromatin architecture, regulation of RNA splicing, and active transcription. We conclude by discussing clinical correlations between domain-specific mutations and RTT pathology to stress that all structural domains of MeCP2 are required to properly mediate cellular function of the intact protein.
    MeSH term(s) Amino Acid Sequence ; Animals ; Genome/genetics ; Humans ; Methyl-CpG-Binding Protein 2/chemistry ; Methyl-CpG-Binding Protein 2/metabolism ; Molecular Sequence Data ; Protein Structure, Tertiary ; Rett Syndrome/metabolism
    Chemical Substances Methyl-CpG-Binding Protein 2
    Language English
    Publishing date 2009-02-23
    Publishing country Canada
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Review
    ZDB-ID 54104-7
    ISSN 0829-8211
    ISSN 0829-8211
    DOI 10.1139/O08-115
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: DNA binding restricts the intrinsic conformational flexibility of methyl CpG binding protein 2 (MeCP2).

    Hansen, Jeffrey C / Wexler, Brian B / Rogers, Danielle J / Hite, Kristopher C / Panchenko, Tanya / Ajith, Sandya / Black, Ben E

    The Journal of biological chemistry

    2011  Volume 286, Issue 21, Page(s) 18938–18948

    Abstract: Mass spectrometry-based hydrogen/deuterium exchange (H/DX) has been used to define the polypeptide backbone dynamics of full-length methyl CpG binding protein 2 (MeCP2) when free in solution and when bound to unmethylated and methylated DNA. Essentially ... ...

    Abstract Mass spectrometry-based hydrogen/deuterium exchange (H/DX) has been used to define the polypeptide backbone dynamics of full-length methyl CpG binding protein 2 (MeCP2) when free in solution and when bound to unmethylated and methylated DNA. Essentially the entire MeCP2 polypeptide chain underwent H/DX at rates faster than could be measured (i.e. complete exchange in ≤10 s), with the exception of the methyl DNA binding domain (MBD). Even the H/DX of the MBD was rapid compared with that of a typical globular protein. Thus, there is no single tertiary structure of MeCP2. Rather, the full-length protein rapidly samples many different conformations when free in solution. When MeCP2 binds to unmethylated DNA, H/DX is slowed several orders of magnitude throughout the MBD. Binding of MeCP2 to methylated DNA led to additional minor H/DX protection, and only locally within the N-terminal portion of the MBD. H/DX also was used to examine the structural dynamics of the isolated MBD carrying three frequent mutations associated with Rett syndrome. The effects of the mutations ranged from very little (R106W) to a substantial increase in conformational sampling (F155S). Our H/DX results have yielded fine resolution mapping of the structure of full-length MeCP2 in the absence and presence of DNA, provided a biochemical basis for understanding MeCP2 function in normal cells, and predicted potential approaches for the treatment of a subset of RTT cases caused by point mutations that destabilize the MBD.
    MeSH term(s) Amino Acid Substitution ; DNA/chemistry ; DNA/genetics ; DNA/metabolism ; DNA Methylation ; Humans ; Methyl-CpG-Binding Protein 2/chemistry ; Methyl-CpG-Binding Protein 2/genetics ; Methyl-CpG-Binding Protein 2/metabolism ; Mutation, Missense ; Peptide Mapping ; Protein Binding ; Protein Conformation ; Protein Stability ; Rett Syndrome/genetics ; Rett Syndrome/metabolism
    Chemical Substances MECP2 protein, human ; Methyl-CpG-Binding Protein 2 ; DNA (9007-49-2)
    Language English
    Publishing date 2011-04-04
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2997-x
    ISSN 1083-351X ; 0021-9258
    ISSN (online) 1083-351X
    ISSN 0021-9258
    DOI 10.1074/jbc.M111.234609
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Unique physical properties and interactions of the domains of methylated DNA binding protein 2.

    Ghosh, Rajarshi P / Nikitina, Tatiana / Horowitz-Scherer, Rachel A / Gierasch, Lila M / Uversky, Vladimir N / Hite, Kristopher / Hansen, Jeffrey C / Woodcock, Christopher L

    Biochemistry

    2010  Volume 49, Issue 20, Page(s) 4395–4410

    Abstract: ... of these flanking domains is also capable of autonomous DNA binding. In contrast, the C-terminal portion ...

    Abstract Methylated DNA binding protein 2 (MeCP2) is a methyl CpG binding protein whose key role is the recognition of epigenetic information encoded in DNA methylation patterns. Mutation or misregulation 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 approximately 60% unstructured, with nine interspersed alpha-molecular recognition features (alpha-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 that 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 that 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 led to new mechanistic and biochemical insights regarding the conformational modulations of this intrinsically disordered protein, and its context-dependent in vivo roles.
    MeSH term(s) Binding Sites ; Chromatin/metabolism ; DNA/metabolism ; Humans ; Methyl-CpG-Binding Protein 2/chemistry ; Methyl-CpG-Binding Protein 2/metabolism ; Methyl-CpG-Binding Protein 2/physiology ; Models, Molecular ; Protein Binding/physiology ; Protein Interaction Domains and Motifs/physiology ; Protein Stability ; Protein Structure, Secondary ; Protein Structure, Tertiary/physiology ; Substrate Specificity ; Temperature
    Chemical Substances Chromatin ; MECP2 protein, human ; Methyl-CpG-Binding Protein 2 ; DNA (9007-49-2)
    Language English
    Publishing date 2010-04-20
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 1108-3
    ISSN 1520-4995 ; 0006-2960
    ISSN (online) 1520-4995
    ISSN 0006-2960
    DOI 10.1021/bi9019753
    Database MEDical Literature Analysis and Retrieval System OnLINE

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