A Structural View of Negative Regulation of the Toll-like Receptor-Mediated Inflammatory Pathway.
Even though the Toll-like receptor (TLR) pathway is integral to inflammatory defense mechanisms, its excessive signaling may be devastating. Cells have acquired a cascade of strategies to regulate TLR signaling by targeting protein-protein interactions, or ubiquitin chains, but the details of the inhibition mechanisms are still unclear. Here, we provide the structural basis for the regulation of TLR signaling by constructing architectures of protein-protein interactions. Structural data suggest that 1) Toll/IL-1R (TIR) domain-containing regulators (BCAP, SIGIRR, and ST2) interfere with TIR domain signalosome formation; 2) major deubiquitinases such as A20, CYLD, and DUBA prevent association of TRAF6 and TRAF3 with their partners, in addition to removing K63-linked ubiquitin chains that serve as a docking platform for downstream effectors; 3) alternative downstream pathways of TLRs also restrict signaling by competing to bind common partners through shared binding sites. We also performed in silico mutagenesis analysis to characterize the effects of oncogenic mutations on the negative regulators and to observe the cellular outcome (whether there is/is not inflammation). Missense mutations that fall on interfaces and nonsense/frameshift mutations that result in truncated negative regulators disrupt the interactions with the targets, thereby enabling constitutive activation of the nuclear factor-kappa B, and contributing to chronic inflammation, autoimmune diseases, and oncogenesis.
Department of Chemical and Biological Engineering, Koc University, Istanbul, Turkey; Center for Computational Biology and Bioinformatics, Koc University, Istanbul, Turkey.
Emine
E
Guven-Maiorov
Department of Chemical and Biological Engineering, Koc University, Istanbul, Turkey; Center for Computational Biology and Bioinformatics, Koc University, Istanbul, Turkey. Electronic address: okeskin@ku.edu.tr.
Ozlem
O
Keskin
Center for Computational Biology and Bioinformatics, Koc University, Istanbul, Turkey; Department of Computer Engineering, Koc University, Istanbul, Turkey.
Attila
A
Gursoy
Cancer and Inflammation Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, National Cancer Institute, Frederick, Maryland; Sackler Institute of Molecular Medicine, Department of Human Genetics and Molecular Medicine, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel. Electronic address: nussinor@helix.nih.gov.
Ruth
R
Nussinov
D017360:Arabidopsis; D001426:Bacterial Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000378:metabolism*; D008958:Models, Molecular; D009154:Mutation; D010231:Paracoccus denitrificans; D010940:Plant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D051193:Toll-Like Receptors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
D001426:Bacterial Proteins; D010940:Plant Proteins; D051193:Toll-Like Receptors