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Structural basis of bloom syndrome (BS) causing mutations in the BLM helicase domain

Rong, SB; Valiaho, J and Vihinen, Mauno LU (2000) In Molecular Medicine 6(3). p.155-164
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. Materials and 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... (More)
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. Materials and 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 stereo chemistry 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 ZA. 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. (Less)
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author
publishing date
type
Contribution to journal
publication status
published
subject
in
Molecular Medicine
volume
6
issue
3
pages
155 - 164
publisher
The Feinstein Institute for Medical Research
external identifiers
  • wos:000087796900002
  • scopus:0034151430
ISSN
1528-3658
language
English
LU publication?
no
id
2d3dfb8e-6a65-4eab-9f86-067e484e4318 (old id 3852232)
date added to LUP
2013-06-28 13:18:18
date last changed
2017-01-01 07:20:11
@article{2d3dfb8e-6a65-4eab-9f86-067e484e4318,
  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. Materials and 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 stereo chemistry 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 ZA. 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.},
  author       = {Rong, SB and Valiaho, J and Vihinen, Mauno},
  issn         = {1528-3658},
  language     = {eng},
  number       = {3},
  pages        = {155--164},
  publisher    = {The Feinstein Institute for Medical Research},
  series       = {Molecular Medicine},
  title        = {Structural basis of bloom syndrome (BS) causing mutations in the BLM helicase domain},
  volume       = {6},
  year         = {2000},
}