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Genome wide analysis of pathogenic SH2 domain mutations.

Lappalainen, Ilkka; Thusberg, Janita; Shen, Bairong and Vihinen, Mauno LU (2008) In Proteins 72(2). p.779-792
Abstract
The authors have made a genome-wide analysis of mutations in Src homology 2 (SH2) domains associated with human disease. Disease-causing mutations have been detected in the SH2 domains of cytoplasmic signaling proteins Bruton tyrosine kinase (BTK), SH2D1A, Ras GTPase activating protein (RasGAP), ZAP-70, SHP-2, STAT1, STAT5B, and the p85alpha subunit of the PIP3. Mutations in the BTK, SH2D1A, ZAP70, STAT1, and STAT5B genes have been shown to cause diverse immunodeficiencies, whereas the mutations in RASA1 and PIK3R1 genes lead to basal carcinoma and diabetes, respectively. PTPN11 mutations cause Noonan sydrome and different types of cancer, depending mainly on whether the mutation is inherited or sporadic. We collected and analyzed all... (More)
The authors have made a genome-wide analysis of mutations in Src homology 2 (SH2) domains associated with human disease. Disease-causing mutations have been detected in the SH2 domains of cytoplasmic signaling proteins Bruton tyrosine kinase (BTK), SH2D1A, Ras GTPase activating protein (RasGAP), ZAP-70, SHP-2, STAT1, STAT5B, and the p85alpha subunit of the PIP3. Mutations in the BTK, SH2D1A, ZAP70, STAT1, and STAT5B genes have been shown to cause diverse immunodeficiencies, whereas the mutations in RASA1 and PIK3R1 genes lead to basal carcinoma and diabetes, respectively. PTPN11 mutations cause Noonan sydrome and different types of cancer, depending mainly on whether the mutation is inherited or sporadic. We collected and analyzed all known pathogenic mutations affecting human SH2 domains by bioinformatics methods. Among the investigated protein properties are sequence conservation and covariance, structural stability, side chain rotamers, packing effects, surface electrostatics, hydrogen bond formation, accessible surface area, salt bridges, and residue contacts. The majority of the mutations affect positions essential for phosphotyrosine ligand binding and specificity. The structural basis of the SH2 domain diseases was elucidated based on the bioinformatic analysis. (Less)
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author
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Protein-Tyrosine Kinases: chemistry, Protein-Tyrosine Kinases: genetics
in
Proteins
volume
72
issue
2
pages
779 - 792
publisher
John Wiley & Sons
external identifiers
  • PMID:18260110
  • Scopus:46449121011
ISSN
0887-3585
DOI
10.1002/prot.21970
language
English
LU publication?
no
id
5e33d3ff-eb5d-4ae1-b3bf-b85c1cb53884 (old id 3635025)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/18260110?dopt=Abstract
date added to LUP
2013-06-12 16:34:50
date last changed
2016-12-04 04:41:40
@misc{5e33d3ff-eb5d-4ae1-b3bf-b85c1cb53884,
  abstract     = {The authors have made a genome-wide analysis of mutations in Src homology 2 (SH2) domains associated with human disease. Disease-causing mutations have been detected in the SH2 domains of cytoplasmic signaling proteins Bruton tyrosine kinase (BTK), SH2D1A, Ras GTPase activating protein (RasGAP), ZAP-70, SHP-2, STAT1, STAT5B, and the p85alpha subunit of the PIP3. Mutations in the BTK, SH2D1A, ZAP70, STAT1, and STAT5B genes have been shown to cause diverse immunodeficiencies, whereas the mutations in RASA1 and PIK3R1 genes lead to basal carcinoma and diabetes, respectively. PTPN11 mutations cause Noonan sydrome and different types of cancer, depending mainly on whether the mutation is inherited or sporadic. We collected and analyzed all known pathogenic mutations affecting human SH2 domains by bioinformatics methods. Among the investigated protein properties are sequence conservation and covariance, structural stability, side chain rotamers, packing effects, surface electrostatics, hydrogen bond formation, accessible surface area, salt bridges, and residue contacts. The majority of the mutations affect positions essential for phosphotyrosine ligand binding and specificity. The structural basis of the SH2 domain diseases was elucidated based on the bioinformatic analysis.},
  author       = {Lappalainen, Ilkka and Thusberg, Janita and Shen, Bairong and Vihinen, Mauno},
  issn         = {0887-3585},
  keyword      = {Protein-Tyrosine Kinases: chemistry,Protein-Tyrosine Kinases: genetics},
  language     = {eng},
  number       = {2},
  pages        = {779--792},
  publisher    = {ARRAY(0xc4f9178)},
  series       = {Proteins},
  title        = {Genome wide analysis of pathogenic SH2 domain mutations.},
  url          = {http://dx.doi.org/10.1002/prot.21970},
  volume       = {72},
  year         = {2008},
}