title: In silico modeling of human α2C-adrenoreceptor interaction with filamin-2.
abstract: Vascular smooth muscle α2C-adrenoceptors (α2C-ARs) mediate vasoconstriction of small blood vessels, especially arterioles. Studies of endogenous receptors in human arteriolar smooth muscle cells (referred to as microVSM) and transiently transfected receptors in heterologous HEK293 cells show that the α2C-ARs are perinuclear receptors that translocate to the cell surface under cellular stress and elicit a biological response. Recent studies in microVSM unraveled a crucial role of Rap1A-Rho-ROCK-F-actin pathways in receptor translocation, and identified protein-protein interaction of α2C-ARs with the actin binding protein filamin-2 as an essential step in the process. To better understand the molecular nature and specificity of this interaction, in this study, we constructed comparative models of human α2C-AR and human filamin-2 proteins. Finally, we performed in silico protein-protein docking to provide a structural platform for the investigation of human α2C-AR and filamin-2 interactions. We found that electrostatic interactions seem to play a key role in this complex formation which manifests in interactions between the C-terminal arginines of α2C-ARs (particularly R454 and R456) and negatively charged residues from filamin-2 region between residues 1979 and 2206. Phylogenetic and sequence analysis showed that these interactions have evolved in warm-blooded animals.
authors.affiliation: Battelle Center for Mathematical Medicine, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, United States of America.
authors.forename: Marcin
authors.initials: M
authors.lastname: Pawlowski
authors.affiliation: Battelle Center for Mathematical Medicine, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, United States of America.
authors.forename: Saras
authors.initials: S
authors.lastname: Saraswathi
authors.affiliation: Center for Cardiovascular and Pulmonary Research, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, United States of America; Department of Pharmacology & Toxicology, Helwan University, Helwan, Egypt.
authors.forename: Hanaa K B
authors.initials: HK
authors.lastname: Motawea
authors.affiliation: Center for Cardiovascular and Pulmonary Research, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, United States of America; Department of Pediatrics, The Ohio State University, Columbus, Ohio, United States of America.
authors.forename: Maqsood A
authors.initials: MA
authors.lastname: Chotani
authors.affiliation: Battelle Center for Mathematical Medicine, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, United States of America; Department of Pediatrics, The Ohio State University, Columbus, Ohio, United States of America.
authors.forename: Andrzej
authors.initials: A
authors.lastname: Kloczkowski
mesh_terms: D000595:Amino Acid Sequence; D003198:Computer Simulation; D064448:Filamins / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D062105:Molecular Docking Simulation; D008969:Molecular Sequence Data; D010802:Phylogeny; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D018341:Receptors, Adrenergic, alpha-2 / Q000737:chemistry / Q000378:metabolism*; D016415:Sequence Alignment; D013379:Substrate Specificity
chemical_list: C578661:FLNC protein, human; D064448:Filamins; D018341:Receptors, Adrenergic, alpha-2
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