TY - JOUR
T1 - Preliminary computational modeling of nitric oxide synthase 3 interactions with caveolin-1
T2 - Influence of exon 7 Glu298Asp polymorphism
AU - Joshi, Mandar S.
AU - Bauer, John Anthony
PY - 2008/1
Y1 - 2008/1
N2 - The significance of endothelial nitric oxide synthase 3 (NOS3) activity has been recognized for many years, however it was only recently that the complicated regulation of this constitutively expressed enzyme in endothelial cells was identified. A critical component of the NOS3 regulatory cycle in endothelial cells is its intracellular localization to caveolae. The caveolar coordination of NOS3, more specifically its interaction with caveolin-1 (Cav-1), plays a major role in normal endothelial NOS3 activity and vascular bioavailability of nitric oxide. We have recently shown that the presence of NOS3 exon 7 Glu298Asp polymorphism caused diminished shear-dependent NOS activation, was less extensively associated with caveolae, and had a decreased degree of interaction with Cav-1. Here, we carried out preliminary investigations to identify possible mechanisms of the genotype-dependent endothelial cell responses we observed in our previous investigations. Through this approach we tested the hypothesis that computer simulations could provide insights regarding the contribution of this single nucleotide polymorphism to regulation of the NOS3 isoform. We observed that in the Glu/Asp and Asp/Asp mutant genotypes, the amount of NOS3 associated with Cav-1 was significantly lower. Additionally, we have shown, using a theoretical computational model, that mutation of an amino acid at position 298 might affect the protein-protein interactions and localization of the NOS3 protein. These alterations might also affect the protein function and explain the enhanced disease risk associated with the presence of Glu298Asp polymorphism in the NOS3 protein.
AB - The significance of endothelial nitric oxide synthase 3 (NOS3) activity has been recognized for many years, however it was only recently that the complicated regulation of this constitutively expressed enzyme in endothelial cells was identified. A critical component of the NOS3 regulatory cycle in endothelial cells is its intracellular localization to caveolae. The caveolar coordination of NOS3, more specifically its interaction with caveolin-1 (Cav-1), plays a major role in normal endothelial NOS3 activity and vascular bioavailability of nitric oxide. We have recently shown that the presence of NOS3 exon 7 Glu298Asp polymorphism caused diminished shear-dependent NOS activation, was less extensively associated with caveolae, and had a decreased degree of interaction with Cav-1. Here, we carried out preliminary investigations to identify possible mechanisms of the genotype-dependent endothelial cell responses we observed in our previous investigations. Through this approach we tested the hypothesis that computer simulations could provide insights regarding the contribution of this single nucleotide polymorphism to regulation of the NOS3 isoform. We observed that in the Glu/Asp and Asp/Asp mutant genotypes, the amount of NOS3 associated with Cav-1 was significantly lower. Additionally, we have shown, using a theoretical computational model, that mutation of an amino acid at position 298 might affect the protein-protein interactions and localization of the NOS3 protein. These alterations might also affect the protein function and explain the enhanced disease risk associated with the presence of Glu298Asp polymorphism in the NOS3 protein.
KW - Caveolin-1
KW - Computational modeling
KW - Gene polymorphism
KW - NOS3
KW - Protein-protein interaction
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U2 - 10.1111/j.1745-7270.2008.00369.x
DO - 10.1111/j.1745-7270.2008.00369.x
M3 - Article
C2 - 18180853
AN - SCOPUS:38349006207
SN - 1672-9145
VL - 40
SP - 47
EP - 54
JO - Acta Biochimica et Biophysica Sinica
JF - Acta Biochimica et Biophysica Sinica
IS - 1
ER -