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Structural basis of ICF-causing mutations in the methyltransferase domain of DNMT3B.

Lappalainen, Ilkka and Vihinen, Mauno LU (2002) In Protein Engineering 15(12). p.1005-1014
Abstract
Mutations in the gene encoding for a de novo methyltransferase, DNMT3B, lead to an autosomal recessive Immunodeficiency, Centromeric instability and Facial anomalies (ICF) syndrome. To analyse the protein structure and consequences of ICF-causing mutations, we modelled the structure of the DNMT3B methyltransferase domain based on Haemophilus haemolyticus protein in complex with the cofactor AdoMet and the target DNA sequence. The structural model has a two-subdomain fold where the DNA-binding region is situated between the subdomains on a surface cleft having positive electrostatic potential. The smaller subdomains of the methyltransferases differ in length and sequences and therefore only the target recognition domain loop was modelled to... (More)
Mutations in the gene encoding for a de novo methyltransferase, DNMT3B, lead to an autosomal recessive Immunodeficiency, Centromeric instability and Facial anomalies (ICF) syndrome. To analyse the protein structure and consequences of ICF-causing mutations, we modelled the structure of the DNMT3B methyltransferase domain based on Haemophilus haemolyticus protein in complex with the cofactor AdoMet and the target DNA sequence. The structural model has a two-subdomain fold where the DNA-binding region is situated between the subdomains on a surface cleft having positive electrostatic potential. The smaller subdomains of the methyltransferases differ in length and sequences and therefore only the target recognition domain loop was modelled to show the location of an ICF-causing mutation. Based on the model, the DNMT3B recognizes the GC sequence and flips the cytosine from the double-stranded DNA to the catalytic pocket. The amino acids in the cofactor and target cytosine binding sites and also the electrostatic properties of the binding pockets are conserved. In addition, a registry of all known ICF-causing mutations, DNMT3Bbase, was constructed. The structural principles of the pathogenic mutations based on the modelled structure and the analysis of chi angle rotation changes of mutated side chains are discussed. (Less)
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author
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Face: abnormalities, Type II Site-Specific: chemistry, Deoxyribonucleases, DNA (Cytosine-5-)-Methyltransferase: metabolism, DNA (Cytosine-5-)-Methyltransferase: chemistry, DNA (Cytosine-5-)-Methyltransferase: genetics, Haemophilus: chemistry, Immunologic Deficiency Syndromes: genetics, S-Adenosylmethionine: chemistry, S-Adenosylmethionine: metabolism
in
Protein Engineering
volume
15
issue
12
pages
1005 - 1014
publisher
Oxford University Press
external identifiers
  • pmid:12601140
  • scopus:0036933456
ISSN
1460-213X
language
English
LU publication?
no
id
4150def6-d943-416e-a362-6303fe44e4aa (old id 3635566)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/12601140?dopt=Abstract
date added to LUP
2013-06-12 16:06:01
date last changed
2017-12-04 15:45:56
@article{4150def6-d943-416e-a362-6303fe44e4aa,
  abstract     = {Mutations in the gene encoding for a de novo methyltransferase, DNMT3B, lead to an autosomal recessive Immunodeficiency, Centromeric instability and Facial anomalies (ICF) syndrome. To analyse the protein structure and consequences of ICF-causing mutations, we modelled the structure of the DNMT3B methyltransferase domain based on Haemophilus haemolyticus protein in complex with the cofactor AdoMet and the target DNA sequence. The structural model has a two-subdomain fold where the DNA-binding region is situated between the subdomains on a surface cleft having positive electrostatic potential. The smaller subdomains of the methyltransferases differ in length and sequences and therefore only the target recognition domain loop was modelled to show the location of an ICF-causing mutation. Based on the model, the DNMT3B recognizes the GC sequence and flips the cytosine from the double-stranded DNA to the catalytic pocket. The amino acids in the cofactor and target cytosine binding sites and also the electrostatic properties of the binding pockets are conserved. In addition, a registry of all known ICF-causing mutations, DNMT3Bbase, was constructed. The structural principles of the pathogenic mutations based on the modelled structure and the analysis of chi angle rotation changes of mutated side chains are discussed.},
  author       = {Lappalainen, Ilkka and Vihinen, Mauno},
  issn         = {1460-213X},
  keyword      = {Face: abnormalities,Type II Site-Specific: chemistry,Deoxyribonucleases,DNA (Cytosine-5-)-Methyltransferase: metabolism,DNA (Cytosine-5-)-Methyltransferase: chemistry,DNA (Cytosine-5-)-Methyltransferase: genetics,Haemophilus: chemistry,Immunologic Deficiency Syndromes: genetics,S-Adenosylmethionine: chemistry,S-Adenosylmethionine: metabolism},
  language     = {eng},
  number       = {12},
  pages        = {1005--1014},
  publisher    = {Oxford University Press},
  series       = {Protein Engineering},
  title        = {Structural basis of ICF-causing mutations in the methyltransferase domain of DNMT3B.},
  volume       = {15},
  year         = {2002},
}