title: The structural pathway of interleukin 1 (IL-1) initiated signaling reveals mechanisms of oncogenic mutations and SNPs in inflammation and cancer.
abstract: Interleukin-1 (IL-1) is a large cytokine family closely related to innate immunity and inflammation. IL-1 proteins are key players in signaling pathways such as apoptosis, TLR, MAPK, NLR and NF-κB. The IL-1 pathway is also associated with cancer, and chronic inflammation increases the risk of tumor development via oncogenic mutations. Here we illustrate that the structures of interfaces between proteins in this pathway bearing the mutations may reveal how. Proteins are frequently regulated via their interactions, which can turn them ON or OFF. We show that oncogenic mutations are significantly at or adjoining interface regions, and can abolish (or enhance) the protein-protein interaction, making the protein constitutively active (or inactive, if it is a repressor). We combine known structures of protein-protein complexes and those that we have predicted for the IL-1 pathway, and integrate them with literature information. In the reconstructed pathway there are 104 interactions between proteins whose three dimensional structures are experimentally identified; only 15 have experimentally-determined structures of the interacting complexes. By predicting the protein-protein complexes throughout the pathway via the PRISM algorithm, the structural coverage increases from 15% to 71%. In silico mutagenesis and comparison of the predicted binding energies reveal the mechanisms of how oncogenic and single nucleotide polymorphism (SNP) mutations can abrogate the interactions or increase the binding affinity of the mutant to the native partner. Computational mapping of mutations on the interface of the predicted complexes may constitute a powerful strategy to explain the mechanisms of activation/inhibition. It can also help explain how an oncogenic mutation or SNP works.
authors.affiliation: Center for Computational Biology and Bioinformatics and College of Engineering, Koc University, Sariyer Istanbul, Turkey.
authors.forename: Saliha Ece
authors.initials: SE
authors.lastname: Acuner Ozbabacan
authors.affiliation: Center for Computational Biology and Bioinformatics and College of Engineering, Koc University, Sariyer Istanbul, Turkey.
authors.forename: Attila
authors.initials: A
authors.lastname: Gursoy
authors.affiliation: Cancer and Inflammation Program, Leidos Biomedical Research, Inc., National Cancer Institute, Frederick National Laboratory, Frederick, Maryland, United States of America ; Sackler Inst. 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: Center for Computational Biology and Bioinformatics and College of Engineering, Koc University, Sariyer Istanbul, Turkey.
authors.forename: Ozlem
authors.initials: O
authors.lastname: Keskin
mesh_terms: D019295:Computational Biology; D003198:Computer Simulation; D006801:Humans; D007249:Inflammation / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism; D007375:Interleukin-1 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D053577:Interleukin-1 Receptor Accessory Protein / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D048670:MAP Kinase Kinase 4 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D048688:MAP Kinase Kinase 7 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D048057:Mitogen-Activated Protein Kinase 10 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D048056:Mitogen-Activated Protein Kinase 9 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D008954:Models, Biological; D008958:Models, Molecular; D016296:Mutagenesis; D009154:Mutation; D009369:Neoplasms / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism; D009857:Oncogenes; D020641:Polymorphism, Single Nucleotide; D060066:Protein Interaction Maps / Q000235:genetics / Q000276:immunology; D053573:Receptors, Interleukin-1 Type I / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
chemical_list: C508590:IL1R1 protein, human; C507765:IL1RAP protein, human; D007375:Interleukin-1; D053577:Interleukin-1 Receptor Accessory Protein; D053573:Receptors, Interleukin-1 Type I; D048057:Mitogen-Activated Protein Kinase 10; D048056:Mitogen-Activated Protein Kinase 9; D048670:MAP Kinase Kinase 4; D048688:MAP Kinase Kinase 7; C482559:MAP2K4 protein, human; C482569:MAP2K7 protein, human