title: Structural basis of Bloom syndrome (BS) causing mutations in the BLM helicase domain.
abstract: BACKGROUND
  Bloom syndrome (BS) is characterized by mutations within the BLM gene. The Bloom syndrome protein (BLM) has similarity to the RecQ subfamily of DNA helicases, which contain seven conserved helicase domains and share significant sequence and structural similarity with the Rep and PcrA DNA helicases. We modeled the three-dimensional structure of the BLM helicase domain to analyze the structural basis of BS-causing mutations.
  
  
  METHODS
  The sequence alignment was performed for RecQ DNA helicases and Rep and PcrA helicases. The crystal structure of PcrA helicase (PDB entry 3PJR) was used as the template for modeling the BLM helicase domain. The model was used to infer the function of BLM and to analyze the effect of the mutations.
  
  
  RESULTS
  The structural model with good stereochemistry of the BLM helicase domain contains two subdomains, 1A and 2A. The electrostatic potential of the model is highly negative over most of the surface, except for the cleft between subdomains 1A and 2A which is similar to the template protein. The ATP-binding site is located inside the model between subdomains 1A and 2A; whereas, the DNA-binding region is situated at the surface cleft, with positive potential between 1A and 2A.
  
  
  CONCLUSIONS
  The three-dimensional structure of the BLM helicase domain was modeled and applied to interpret BS-causing mutations. The mutation I841T is likely to weaken DNA binding, while the mutations C891R, C901Y, and Q672R presumably disturb the ATP binding. In addition, other critical positions are discussed.
authors.affiliation: Institute of Medical Technology, University of Tampere, Finland.
authors.forename: S B
authors.initials: SB
authors.lastname: Rong
authors.forename: J
authors.initials: J
authors.lastname: Väliaho
authors.forename: M
authors.initials: M
authors.lastname: Vihinen
mesh_terms: D000251:Adenosine Triphosphatases / Q000737:chemistry* / Q000235:genetics*; D000595:Amino Acid Sequence; D001426:Bacterial Proteins / Q000235:genetics; D001665:Binding Sites; D001816:Bloom Syndrome / Q000201:enzymology* / Q000235:genetics*; D004265:DNA Helicases / Q000737:chemistry* / Q000235:genetics*; D016208:Databases, Factual; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D017434:Protein Structure, Tertiary / Q000235:genetics; D053484:RecQ Helicases; D017386:Sequence Homology, Amino Acid; D055672:Static Electricity
chemical_list: D001426:Bacterial Proteins; C084217:pcrA protein, Bacteria; D000251:Adenosine Triphosphatases; C097151:Bloom syndrome protein; C506725:RECQL protein, human; D004265:DNA Helicases; D053484:RecQ Helicases