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Understanding the functional difference between growth arrest-specific protein 6 and protein S: an evolutionary approach.

Studer RA, Opperdoes FR, Nicolaes GA, Mulder AB, Mulder R - Open Biol (2014)

Bottom Line: Sites experiencing functional divergence tend to express a greater diversity of stabilizing/destabilizing effects than sites that do not experience such functional divergence.Three electrostatic patches in the LG1/LG2 domains were found to differ between GAS6 and PROS1.These results may help researchers to analyse disease-causing mutations in the light of evolutionary and structural constraints, and link genetic pathology to clinical phenotypes.

View Article: PubMed Central - PubMed

Affiliation: European Molecular Biology Laboratory-European Bioinformatics Institute (EMBL-EBI), Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SD, UK.

ABSTRACT
Although protein S (PROS1) and growth arrest-specific protein 6 (GAS6) proteins are homologous with a high degree of structural similarity, they are functionally different. The objectives of this study were to identify the evolutionary origins from which these functional differences arose. Bioinformatics methods were used to estimate the evolutionary divergence time and to detect the amino acid residues under functional divergence between GAS6 and PROS1. The properties of these residues were analysed in the light of their three-dimensional structures, such as their stability effects, the identification of electrostatic patches and the identification potential protein-protein interaction. The divergence between GAS6 and PROS1 probably occurred during the whole-genome duplications in vertebrates. A total of 78 amino acid sites were identified to be under functional divergence. One of these sites, Asn463, is involved in N-glycosylation in GAS6, but is mutated in PROS1, preventing this post-translational modification. Sites experiencing functional divergence tend to express a greater diversity of stabilizing/destabilizing effects than sites that do not experience such functional divergence. Three electrostatic patches in the LG1/LG2 domains were found to differ between GAS6 and PROS1. Finally, a surface responsible for protein-protein interactions was identified. These results may help researchers to analyse disease-causing mutations in the light of evolutionary and structural constraints, and link genetic pathology to clinical phenotypes.

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Visualization of electrostatic surfaces on the SHBG-domain of PROS1 and GAS6. To make the direct comparison between GAS6 and PROS1 easier, we have modelled their SHBG domains using the GAS6 PDB structure (PDB ID: 2C5D). NAG ligand has been added to identify its putative binding pocket. While it is crystallized in GAS6, there is no evidence to indicate whether it can be present in PROS1. Basic surfaces are in blue while acidic surfaces are in red. The NAG ligand is in green. The green circles indicate the observed differences in electrostatic surface potential between GAS6 and PROS1.
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RSOB140121F6: Visualization of electrostatic surfaces on the SHBG-domain of PROS1 and GAS6. To make the direct comparison between GAS6 and PROS1 easier, we have modelled their SHBG domains using the GAS6 PDB structure (PDB ID: 2C5D). NAG ligand has been added to identify its putative binding pocket. While it is crystallized in GAS6, there is no evidence to indicate whether it can be present in PROS1. Basic surfaces are in blue while acidic surfaces are in red. The NAG ligand is in green. The green circles indicate the observed differences in electrostatic surface potential between GAS6 and PROS1.

Mentions: Using APBS [66] to compute the electrostatic properties of the surfaces of the SHBG domain, we observed three patches that are different between PROS1 and GAS6 (figure 6).FigureĀ 6.


Understanding the functional difference between growth arrest-specific protein 6 and protein S: an evolutionary approach.

Studer RA, Opperdoes FR, Nicolaes GA, Mulder AB, Mulder R - Open Biol (2014)

Visualization of electrostatic surfaces on the SHBG-domain of PROS1 and GAS6. To make the direct comparison between GAS6 and PROS1 easier, we have modelled their SHBG domains using the GAS6 PDB structure (PDB ID: 2C5D). NAG ligand has been added to identify its putative binding pocket. While it is crystallized in GAS6, there is no evidence to indicate whether it can be present in PROS1. Basic surfaces are in blue while acidic surfaces are in red. The NAG ligand is in green. The green circles indicate the observed differences in electrostatic surface potential between GAS6 and PROS1.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4221892&req=5

RSOB140121F6: Visualization of electrostatic surfaces on the SHBG-domain of PROS1 and GAS6. To make the direct comparison between GAS6 and PROS1 easier, we have modelled their SHBG domains using the GAS6 PDB structure (PDB ID: 2C5D). NAG ligand has been added to identify its putative binding pocket. While it is crystallized in GAS6, there is no evidence to indicate whether it can be present in PROS1. Basic surfaces are in blue while acidic surfaces are in red. The NAG ligand is in green. The green circles indicate the observed differences in electrostatic surface potential between GAS6 and PROS1.
Mentions: Using APBS [66] to compute the electrostatic properties of the surfaces of the SHBG domain, we observed three patches that are different between PROS1 and GAS6 (figure 6).FigureĀ 6.

Bottom Line: Sites experiencing functional divergence tend to express a greater diversity of stabilizing/destabilizing effects than sites that do not experience such functional divergence.Three electrostatic patches in the LG1/LG2 domains were found to differ between GAS6 and PROS1.These results may help researchers to analyse disease-causing mutations in the light of evolutionary and structural constraints, and link genetic pathology to clinical phenotypes.

View Article: PubMed Central - PubMed

Affiliation: European Molecular Biology Laboratory-European Bioinformatics Institute (EMBL-EBI), Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SD, UK.

ABSTRACT
Although protein S (PROS1) and growth arrest-specific protein 6 (GAS6) proteins are homologous with a high degree of structural similarity, they are functionally different. The objectives of this study were to identify the evolutionary origins from which these functional differences arose. Bioinformatics methods were used to estimate the evolutionary divergence time and to detect the amino acid residues under functional divergence between GAS6 and PROS1. The properties of these residues were analysed in the light of their three-dimensional structures, such as their stability effects, the identification of electrostatic patches and the identification potential protein-protein interaction. The divergence between GAS6 and PROS1 probably occurred during the whole-genome duplications in vertebrates. A total of 78 amino acid sites were identified to be under functional divergence. One of these sites, Asn463, is involved in N-glycosylation in GAS6, but is mutated in PROS1, preventing this post-translational modification. Sites experiencing functional divergence tend to express a greater diversity of stabilizing/destabilizing effects than sites that do not experience such functional divergence. Three electrostatic patches in the LG1/LG2 domains were found to differ between GAS6 and PROS1. Finally, a surface responsible for protein-protein interactions was identified. These results may help researchers to analyse disease-causing mutations in the light of evolutionary and structural constraints, and link genetic pathology to clinical phenotypes.

Show MeSH