title: Tandem Domains with Tuned Interactions Are a Powerful Biological Design Principle.
abstract: Allosteric effects of mutations, ligand binding, or post-translational modifications on protein function occur through changes to the protein's shape, or conformation. In a cell, there are many copies of the same protein, all experiencing these perturbations in a dynamic fashion and fluctuating through different conformations and activity states. According to the "conformational selection and population shift" theory, ligand binding selects a particular conformation. This perturbs the ensemble and induces a population shift. In a new PLOS Biology paper, Melacini and colleagues describe a novel model of protein regulation, the "Double-Conformational Selection Model", which demonstrates how two tandem ligand-binding domains interact to regulate protein function. Here we explain how tandem domains with tuned interactions-but not single domains-can provide a blueprint for sensitive activation sensors within a narrow window of ligand concentration, thereby promoting signaling control.
authors.affiliation: Cancer and Inflammation Program, Leidos Biomedical Research, Inc., Frederick, Maryland, United States of America.|Frederick National Laboratory for Cancer Research, National Cancer Institute, Frederick, Maryland, United States of America.|Sackler Institute of Molecular Medicine, Department of Human Genetics and Molecular Medicine, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Ruth
authors.initials: R
authors.lastname: Nussinov
authors.affiliation: Cancer and Inflammation Program, Leidos Biomedical Research, Inc., Frederick, Maryland, United States of America.|Frederick National Laboratory for Cancer Research, National Cancer Institute, Frederick, Maryland, United States of America.
authors.forename: Chung-Jung
authors.initials: CJ
authors.lastname: Tsai
mesh_terms: D000818:Animals; D054751:Cyclic AMP-Dependent Protein Kinase Catalytic Subunits / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D054756:Cyclic AMP-Dependent Protein Kinase RIalpha Subunit / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D004789:Enzyme Activation; D004798:Enzymes / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D019143:Evolution, Molecular; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D009154:Mutation; D011487:Protein Conformation; D054730:Protein Interaction Domains and Motifs; D021122:Protein Subunits / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D020080:Tandem Repeat Sequences
chemical_list: D054756:Cyclic AMP-Dependent Protein Kinase RIalpha Subunit; D004798:Enzymes; D008024:Ligands; D021122:Protein Subunits; D054751:Cyclic AMP-Dependent Protein Kinase Catalytic Subunits