DP00539: Methyl-CpG-binding protein 2 [Isoform A (Beta)]FASTA viewXML view

General information
DisProt:DP00539
Name:Methyl-CpG-binding protein 2 [Isoform A (Beta)]
Synonym(s):MECP2_HUMAN
MeCp-2 protein
MeCp2
hMeCp2
First appeared in release:Release 3.7 (01/28/2008)
UniProt:P51608
UniGene:Hs.200716
SwissProt: MECP2_HUMAN
TrEMBL:  
NCBI (GI): 1708973
Source organism:Homo sapiens (Human)
Sequence length:486
Percent disordered:91%
Homologues: 


Native sequence

        10         20         30         40         50         60
         |          |          |          |          |          |
MVAGMLGLRE EKSEDQDLQG LKDKPLKFKK VKKDKKEEKE GKHEPVQPSA HHSAEPAEAG - 60
KAETSEGSGS APAVPEASAS PKQRRSIIRD RGPMYDDPTL PEGWTRKLKQ RKSGRSAGKY - 120
DVYLINPQGK AFRSKVELIA YFEKVGDTSL DPNDFDFTVT GRGSPSRREQ KPPKKPKSPK - 180
APGTGRGRGR PKGSGTTRPK AATSEGVQVK RVLEKSPGKL LVKMPFQTSP GGKAEGGGAT - 240
TSTQVMVIKR PGRKRKAEAD PQAIPKKRGR KPGSVVAAAA AEAKKKAVKE SSIRSVQETV - 300
LPIKKRKTRE TVSIEVKEVV KPLLVSTLGE KSGKGLKTCK SPGRKSKESS PKGRSSSASS - 360
PPKKEHHHHH HHSESPKAPV PLLPPLPPPP PEPESSEDPT SPPEPQDLSS SVCKEEKMPR - 420
GGSLESDGCP KEPAKTQPAV ATAATAAEKY KHRGEGERKD IVSSSMPRPN REEPVDSRTP - 480
VTERVS



Functional narrative    

Methyl CpG-binding protein 2 (MeCP2) is a 53-kDa nuclear protein named for its methylated DNA-binding capacity. It can preferentially recognize methylated DNA and act as a methylation-dependent transcriptional repressor in vitro and in vivo. MeCP2 is also involved in the maintenance of condensed chromosomal superstructures and regulates mRNA splicing in vivo. It is able to interact with many different macromolecules and macromolecular complexes, including unmethylated and methylated DNA, nucleosomes and chromatin, transcriptional co-repressors, a histone H3 methyltransferase, Dnmt1 DNA methyltransferase, PU.1, Y box-binding protein 1 and other splicing factors. MeCP2 has two well defined functional domains. Residues 78-162 are required to specifically recognize methylated CpG dinucleotides and have been termed the methyl DNA binding domain (MBD). The minimal sequence needed to repress transfected DNA has been called the transcriptional repression domain (TRD) and consists of residues 207-310. The importance of MeCP2 function is underscored by its central role in the neurological disorder, Rett Syndrome, which is caused by a number of different nonsense, missense, and frameshift mutations scattered throughout the Mecp2 gene. Chromosomal protein that binds to methylated DNA. It can bind specifically to a single methyl-CpG pair. It is not influenced by sequences flanking the methyl-CpGs. Mediates transcriptional repression through interaction with histone deacetylase and the corepressor SIN3A.

Region 1: 2-77 Region 6: 1-90 Region 2: 78-102 Region 3: 145-162 Region 7: 75-164 Region 4: 163-206 Region 8: 165-210 Region 5: 207-310 Region 9: 261-330 Region 10: 335-486

Map of ordered and disordered regions







Note: 'Mouse' over a region to see the start and stop residues. Click on a region to see detailed information.


Region 1
Type:Disordered
Name:High mobility group-like domain 2 (HMGD1)
Location:2 - 77
Length:76
Region sequence:

VAGMLGLREEKSEDQDLQGLKDKPLKFKKVKKDKKEEKEGKHEPVQPSAHHSAEPAEAGK
AETSEGSGSAPAVPEA

Modification type: Native
PDB:  
Structural/functional type:  
Functional classes:  
Functional subclasses:  
Detection methods:
  1. Analytical ultracentrifugation (293 K; )

  2. Circular dichroism (CD) spectroscopy, far-UV (293 K; pH: 7.9; K2HPO4 10 mM; NaCl 20 mM)
References:
  1. Adams VH, McBryant SJ, Wade PA, Woodcock CL, Hansen JC. "Intrinsic disorder and autonomous domain function in the multifunctional nuclear protein, MeCP2." J Biol Chem. 2007; 282(20): 15057-64. PubMed: 17371874
Comments:
 



Region 2
Type:Disordered
Name: 
Location:78 - 102
Length:25
Region sequence:

SASPKQRRSIIRDRGPMYDDPTLPE

Modification type: Engineered
Fragment
PDB:  
Structural/functional type: Function arises from the disordered state
Functional classes:  
Functional subclasses: Protein-protein binding
Detection methods:
  1. Circular dichroism (CD) spectroscopy, far-UV (293 K; pH: 7.9; K2HPO4 10 mM; NaCl 20 mM)
References:
  1. Adams VH, McBryant SJ, Wade PA, Woodcock CL, Hansen JC. "Intrinsic disorder and autonomous domain function in the multifunctional nuclear protein, MeCP2." J Biol Chem. 2007; 282(20): 15057-64. PubMed: 17371874
Comments:
 



Region 3
Type:Disordered
Name: 
Location:145 - 162
Length:18
Region sequence:

VGDTSLDPNDFDFTVTGR

Modification type: Engineered
Fragment
PDB:  
Structural/functional type:  
Functional classes:  
Functional subclasses:  
Detection methods:
  1. Circular dichroism (CD) spectroscopy, far-UV (293 K; pH: 7.9; K2HPO4 10 mM; NaCl 20 mM)
References:
  1. Adams VH, McBryant SJ, Wade PA, Woodcock CL, Hansen JC. "Intrinsic disorder and autonomous domain function in the multifunctional nuclear protein, MeCP2." J Biol Chem. 2007; 282(20): 15057-64. PubMed: 17371874
Comments:
 



Region 4
Type:Disordered
Name:High mobility group-like domain 2 (HMGD2)
Location:163 - 206
Length:44
Region sequence:

GSPSRREQKPPKKPKSPKAPGTGRGRGRPKGSGTTRPKAATSEG

Modification type: Native
PDB:  
Structural/functional type: Function arises from the disordered state
Functional classes:  
Functional subclasses: Nuclear localization
Protein-protein binding
Detection methods:
  1. Circular dichroism (CD) spectroscopy, far-UV (293 K; pH: 7.9; K2HPO4 10 mM; NaCl 20 mM)

  2. Analytical ultracentrifugation (293 K; )
References:
  1. Adams VH, McBryant SJ, Wade PA, Woodcock CL, Hansen JC. "Intrinsic disorder and autonomous domain function in the multifunctional nuclear protein, MeCP2." J Biol Chem. 2007; 282(20): 15057-64. PubMed: 17371874
Comments:
 



Region 5
Type:Disordered
Name:Transcriptional repression domain (TRD)
Location:207 - 310
Length:104
Region sequence:

VQVKRVLEKSPGKLLVKMPFQTSPGGKAEGGGATTSTQVMVIKRPGRKRKAEADPQAIPK
KRGRKPGSVVAAAAAEAKKKAVKESSIRSVQETVLPIKKRKTRE

Modification type: Engineered
Fragment
PDB:  
Structural/functional type: Function arises via a disorder to order transition
Functional classes: Molecular recognition effectors
Functional subclasses: Intraprotein interaction
Protein-DNA binding
Protein-protein binding
Detection methods:
  1. Circular dichroism (CD) spectroscopy, far-UV (293 K; pH: 7.9; K2HPO4 10 mM; NaCl 20 mM)

  2. Electrophoretic Mobility Shift Assay (EMSA) (277 K; Binding buffer (RT, pH 7.4); DNA/NA (methylated or unmethylated) 200 ng; polypeptide construct, varying amts. (TRD, TRD-CTD{alpha} or TRD-CTD{alpha}-CTD{beta}); TAE (buffer, pH8.3); unmethylated DNA competitor or mononucleosome (added when DNA or NA used as substrate) 400 ng)
References:
  1. Adams VH, McBryant SJ, Wade PA, Woodcock CL, Hansen JC. "Intrinsic disorder and autonomous domain function in the multifunctional nuclear protein, MeCP2." J Biol Chem. 2007; 282(20): 15057-64. PubMed: 17371874

  2. Ghosh RP, Nikitina T, Horowitz-Scherer RA, Gierasch LM, Uversky VN, Hite K, Hansen JC, Woodcock CL. "Unique physical properties and interactions of the domains of methylated DNA binding protein 2." Biochemistry. 2010; 49(20): 4395-410. PubMed: 20405910
Comments:
Ghosh, et al. (2010), found a disorder-to-order structure/function relationship for the TRD.


Region 6
Type:Disordered
Name:N-terminal domain (NTD)
Location:1 - 90
Length:90
Region sequence:

MVAGMLGLREEKSEDQDLQGLKDKPLKFKKVKKDKKEEKEGKHEPVQPSAHHSAEPAEAG
KAETSEGSGSAPAVPEASASPKQRRSIIRD

Modification type: Engineered
Fragment
PDB:  
Structural/functional type: Function arises from the disordered state
Functional classes: Molecular recognition effectors
Functional subclasses: Intraprotein interaction
Detection methods:
  1. Circular dichroism (CD) spectroscopy, far-UV

  2. Electrophoretic Mobility Shift Assay (EMSA) (277 K; Binding buffer (RT, pH 7.4); DNA/NA (methylated or unmethylated) 200 ng; polypeptide construct, varying amts. (NTD, NTD-MBD or NTD-MBD-ID); TAE (buffer, pH 8.3); unmethylated DNA competitor or mononucleosome (added when DNA or NA used as substrate) 400 ng)
References:
  1. Ghosh RP, Nikitina T, Horowitz-Scherer RA, Gierasch LM, Uversky VN, Hite K, Hansen JC, Woodcock CL. "Unique physical properties and interactions of the domains of methylated DNA binding protein 2." Biochemistry. 2010; 49(20): 4395-410. PubMed: 20405910
Comments:
Ghosh, et al. (2010), found that MBD activity is enhanced by its flanking domains of NTD and ID.


Region 7
Type:Ordered
Name:Methylated-DNA Binding Domain (MBD)
Location:75 - 164
Length:90
Region sequence:

PEASASPKQRRSIIRDRGPMYDDPTLPEGWTRKLKQRKSGRSAGKYDVYLINPQGKAFRS
KVELIAYFEKVGDTSLDPNDFDFTVTGRGS

Modification type: Engineered
Fragment
PDB: 3C2I:A
Structural/functional type: Function arises from the ordered state
Functional classes: Molecular recognition effectors
Functional subclasses: Intraprotein interaction
Protein-DNA binding
Protein-protein binding
Detection methods:
  1. Circular dichroism (CD) spectroscopy, far-UV

  2. Electrophoretic Mobility Shift Assay (EMSA) (277 K; Binding buffer (RT, pH 7.4); DNA/NA (methylated or unmethylated) 200 ng; polypeptide construct, varying amts. (MBD, NTD-MBD, MBD-ID or NTD-MBD-ID); TAE (buffer, pH 8.3); unmethylated DNA competitor or mononucleosome (added when DNA or NA used as substrate) 400 ng)
References:
  1. Ghosh RP, Nikitina T, Horowitz-Scherer RA, Gierasch LM, Uversky VN, Hite K, Hansen JC, Woodcock CL. "Unique physical properties and interactions of the domains of methylated DNA binding protein 2." Biochemistry. 2010; 49(20): 4395-410. PubMed: 20405910
Comments:
Ghosh, et al. (2010), found that MBD activity is enhanced by its flanking domains of NTD and ID.


Region 8
Type:Disordered
Name:Intervening Domain (ID)
Location:165 - 210
Length:46
Region sequence:

PSRREQKPPKKPKSPKAPGTGRGRGRPKGSGTTRPKAATSEGVQVK

Modification type: Engineered
Fragment
PDB:  
Structural/functional type: Function arises via a disorder to order transition
Functional classes: Molecular recognition effectors
Functional subclasses: Intraprotein interaction
Protein-DNA binding
Detection methods:
  1. Circular dichroism (CD) spectroscopy, far-UV

  2. Electrophoretic Mobility Shift Assay (EMSA) (277 K; Binding buffer (RT, pH 7.4); DNA/NA (methylated or unmethylated) 200 ng; polypeptide construct, varying amts. (ID, MBD-ID or NTD-MBD-ID); TAE (buffer, pH 8.3); unmethylated DNA competitor or mononucleosome (added when DNA or NA used as substrate) 400 ng)
References:
  1. Ghosh RP, Nikitina T, Horowitz-Scherer RA, Gierasch LM, Uversky VN, Hite K, Hansen JC, Woodcock CL. "Unique physical properties and interactions of the domains of methylated DNA binding protein 2." Biochemistry. 2010; 49(20): 4395-410. PubMed: 20405910
Comments:
Ghosh, et al. (2010), found that MBD activity is enhanced by its flanking domains of NTD and ID.


Region 9
Type:Disordered
Name:C-terminal domain, alpha subunit (CTD-alpha)
Location:261 - 330
Length:70
Region sequence:

PQAIPKKRGRKPGSVVAAAAAEAKKKAVKESSIRSVQETVLPIKKRKTRETVSIEVKEVV
KPLLVSTLGE

Modification type: Engineered
Fragment
PDB:  
Structural/functional type: Relationship to function unknown
Functional classes: Molecular recognition effectors
Functional subclasses: Intraprotein interaction
Protein-DNA binding
Protein-protein binding
Detection methods:
  1. Circular dichroism (CD) spectroscopy, far-UV

  2. Electrophoretic Mobility Shift Assay (EMSA) (277 K; Binding buffer (RT, pH 7.4); DNA/NA (methylated or unmethylated) 200 ng; polypeptide construct, varying amts. (CTD{alpha} or TRD-CTD{alpha}-CTD{beta}); TAE (buffer, pH 8.3); unmethylated DNA competitor or mononucleosome (added when DNA or NA used as substrate) 400 ng)
References:
  1. Ghosh RP, Nikitina T, Horowitz-Scherer RA, Gierasch LM, Uversky VN, Hite K, Hansen JC, Woodcock CL. "Unique physical properties and interactions of the domains of methylated DNA binding protein 2." Biochemistry. 2010; 49(20): 4395-410. PubMed: 20405910
Comments:
 



Region 10
Type:Disordered
Name:C-terminal domain, beta subunit (CTD-beta)
Location:335 - 486
Length:152
Region sequence:

GLKTCKSPGRKSKESSPKGRSSSASSPPKKEHHHHHHHSESPKAPVPLLPPLPPPPPEPE
SSEDPTSPPEPQDLSSSVCKEEKMPRGGSLESDGCPKEPAKTQPAVATAATAAEKYKHRG
EGERKDIVSSSMPRPNREEPVDSRTPVTERVS

Modification type: Engineered
Fragment
PDB:  
Structural/functional type:  
Functional classes: Molecular recognition effectors
Functional subclasses: Intraprotein interaction
Protein-DNA binding
Protein-protein binding
Detection methods:
  1. Circular dichroism (CD) spectroscopy, far-UV

  2. Electrophoretic Mobility Shift Assay (EMSA) (277 K; Binding buffer (RT, pH 7.4); DNA/NA (methylated or unmethylated) 200 ng; polypeptide construct, varying amts. (CTD{beta} or TRD-CTD{alpha}-CTD{beta}); TAE (buffer, pH 8.3); unmethylated DNA competitor or mononucleosome (added when DNA or NA used as substrate) 400 ng)
References:
  1. Ghosh RP, Nikitina T, Horowitz-Scherer RA, Gierasch LM, Uversky VN, Hite K, Hansen JC, Woodcock CL. "Unique physical properties and interactions of the domains of methylated DNA binding protein 2." Biochemistry. 2010; 49(20): 4395-410. PubMed: 20405910
Comments:
Ghosh, et al. (2010), found that CTD-beta bound to nucleosomal arrays (NA) but not to pure DNA by itself.


References

  1. Adams VH, McBryant SJ, Wade PA, Woodcock CL, Hansen JC. "Intrinsic disorder and autonomous domain function in the multifunctional nuclear protein, MeCP2." J Biol Chem. 2007; 282(20): 15057-64. PubMed: 17371874

  2. Ghosh RP, Nikitina T, Horowitz-Scherer RA, Gierasch LM, Uversky VN, Hite K, Hansen JC, Woodcock CL. "Unique physical properties and interactions of the domains of methylated DNA binding protein 2." Biochemistry. 2010; 49(20): 4395-410. PubMed: 20405910



Comments


Ghosh, et al. (2010), found that MeCP2 consists of six domains, and divides into two functional units. The NTD-MBD-ID unit functions in methylation-dependent and methylation-independent DNA binding, while the TRD-CTD{alpha}-CTD{beta} unit functions in chromatin compaction and oligomerization. The domains of each unit interact synergistically.


AV (7-7-2010) PubMed: 17371874


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