title: An in silico approach to investigate the source of the controversial interpretations about the phenotypic results of the human AhR-gene G1661A polymorphism.
abstract: Aryl hydrocarbon receptor (AhR) acts as an enhancer binding ligand-activated intracellular receptor. Chromatin remodeling components and general transcription factors such as TATA-binding protein (TBP) are evoked on AhR-target genes by interaction with its flexible transactivation domain (TAD). AhR-G1661A single nucleotide polymorphism (SNP: rs2066853) causes an arginine to lysine substitution in the acidic sub-domain of TAD at position 554 (R554K). Although, numerous studies associate the SNP with some abnormalities such as cancer, other reliable investigations refuse the associations. Consequently, the interpretation of the phenotypic results of G1661A-transition has been controversial. In this study, an in silico analysis were performed to investigate the possible effects of the transition on AhR-mRNA, protein structure, interaction properties and modifications. The analysis revealed that the R554K substitution affects secondary structure and solvent accessibility of adjacent residues. Also, it causes to decreasing of the AhR stability; altering the hydropathy features of the local sequence and changing the pattern of the residues at the binding site of the TAD-acidic sub-domain. Generating of new sites for ubiquitination and acetylation for AhR-K554 variant respectively at positions 544 and 560 was predicted. Our findings intensify the idea that the AhR-G1661A transition may affects AhR-TAD interactions, especially with the TBP, which influence AhR-target genes expression. However, the previously reported flexibility of the modular TAD could act as an intervening factor, moderate the SNP effects and causes distinct outcomes in different individuals and tissues.
authors.affiliation: Department of Molecular and Cell Biology, Faculty of Basic Sciences, University of Mazandaran, Babolsar, Post Code: 47416-95447, Mazandaran, Iran.
authors.forename: Younes
authors.initials: Y
authors.lastname: Aftabi
authors.affiliation: Department of Molecular and Cell Biology, Faculty of Basic Sciences, University of Mazandaran, Babolsar, Post Code: 47416-95447, Mazandaran, Iran. Electronic address: ahcolagar@umz.ac.ir.
authors.forename: Abasalt Hosseinzadeh
authors.initials: AH
authors.lastname: Colagar
authors.affiliation: Department of Life Science Engineering, Faculty of New Sciences & Technologies, University of Tehran, P.O. Box: 14395-1561, Tehran, Iran.
authors.forename: Faramarz
authors.initials: F
authors.lastname: Mehrnejad
mesh_terms: D000595:Amino Acid Sequence; D019943:Amino Acid Substitution / Q000235:genetics; D001483:Base Sequence; D051792:Basic Helix-Loop-Helix Proteins / Q000737:chemistry / Q000235:genetics*; D003198:Computer Simulation; D006801:Humans; D008969:Molecular Sequence Data; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D017510:Protein Folding; D060066:Protein Interaction Maps / Q000235:genetics; D011499:Protein Processing, Post-Translational / Q000235:genetics; D017433:Protein Structure, Secondary; D018336:Receptors, Aryl Hydrocarbon / Q000737:chemistry / Q000235:genetics*; D012984:Software; D054875:Ubiquitination / Q000235:genetics
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D018336:Receptors, Aryl Hydrocarbon; C111235:AHR protein, human
keywords: Aryl hydrocarbon receptor; Post translational modification; Protein–protein interaction; Rs2066853 polymorphism