title: Understanding the functional difference between growth arrest-specific protein 6 and protein S: an evolutionary approach.
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.
authors.affiliation: European Molecular Biology Laboratory-European Bioinformatics Institute (EMBL-EBI), Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SD, UK.
authors.forename: Romain A
authors.initials: RA
authors.lastname: Studer
authors.affiliation: Laboratory of Biochemistry, de Duve Institute and Université catholique de Louvain, Brussels 1200, Belgium.
authors.forename: Fred R
authors.initials: FR
authors.lastname: Opperdoes
authors.affiliation: Department of Biochemistry, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, The Netherlands.
authors.forename: Gerry A F
authors.initials: GA
authors.lastname: Nicolaes
authors.affiliation: Department of Laboratory Medicine, University Medical Centre Groningen, Groningen, The Netherlands.
authors.forename: André B
authors.initials: AB
authors.lastname: Mulder
authors.affiliation: Department of Laboratory Medicine, University Medical Centre Groningen, Groningen, The Netherlands r.mulder01@umcg.nl.
authors.forename: René
authors.initials: R
authors.lastname: Mulder
mesh_terms: D000465:Algorithms; D000596:Amino Acids / Q000737:chemistry; D000818:Animals; D001665:Binding Sites; D001798:Blood Proteins / Q000378:metabolism*; D002938:Ciona intestinalis / Q000378:metabolism; D019295:Computational Biology; D030562:Databases, Protein; D019143:Evolution, Molecular; D006031:Glycosylation; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D009154:Mutation; D010641:Phenotype; D010802:Phylogeny; D011485:Protein Binding; D025941:Protein Interaction Mapping; D011499:Protein Processing, Post-Translational; D017293:Protein S; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D055672:Static Electricity; D000099255:Growth Arrest-Specific Protein 6
chemical_list: D000596:Amino Acids; D001798:Blood Proteins; D036341:Intercellular Signaling Peptides and Proteins; D017293:Protein S; D000099255:Growth Arrest-Specific Protein 6; C523390:PROS1 protein, human
keywords: evolution; growth arrest-specific protein 6; protein S