title: Inhibition of Toll-like receptors TLR4 and 7 signaling pathways by SIGIRR: a computational approach.
abstract: Toll-like receptors (TLRs) belong to the Toll-like receptor/interleukin-1 receptor (TLR/IL-1R) superfamily which is defined by a common cytoplasmic Toll/interleukin-1 receptor (TIR) domain. TLRs recognize pathogen-associated molecular patterns and initiate an intracellular kinase cascade to trigger an immediate defensive response. SIGIRR (single immunoglobulin interleukin-1 receptor-related molecule), another member of the TLR/IL-1R superfamily, acts as a negative regulator of MyD88-dependent TLR signaling. It attenuates the recruitment of MyD88 adaptors to the receptors with its intracellular TIR domain. Thus, SIGIRR is a highly important molecule for the therapy of autoimmune diseases caused by TLRs. So far, the structural mechanism of interactions between SIGIRR, TLRs and adaptor molecules is unclear. To develop a working hypothesis for this interaction, we constructed three-dimensional models for the TIR domains of TLR4, TLR7, MyD88 and SIGIRR based on computational modeling. Through protein-protein docking analysis, we developed models of essential complexes involved in the TLR4 and 7 signaling and the SIGIRR inhibiting processes. We suggest that SIGIRR may exert its inhibitory effect through blocking the molecular interface of TLR4, TLR7 and the MyD88 adaptor mainly via its BB-loop region.
authors.affiliation: Center for Nanoscience, Ludwig-Maximilians-Universität München, 80799 Munich, Germany.
authors.forename: Jing
authors.initials: J
authors.lastname: Gong
authors.forename: Tiandi
authors.initials: T
authors.lastname: Wei
authors.forename: Robert W
authors.initials: RW
authors.lastname: Stark
authors.forename: Ferdinand
authors.initials: F
authors.lastname: Jamitzky
authors.forename: Wolfgang M
authors.initials: WM
authors.lastname: Heckl
authors.forename: Hans J
authors.initials: HJ
authors.lastname: Anders
authors.forename: Maciej
authors.initials: M
authors.lastname: Lech
authors.forename: Shaila C
authors.initials: SC
authors.lastname: Rössle
mesh_terms: D000595:Amino Acid Sequence; D001327:Autoimmune Diseases / Q000378:metabolism; D019295:Computational Biology / Q000379:methods*; D008562:Membrane Glycoproteins / Q000737:chemistry / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011485:Protein Binding; D055503:Protein Multimerization; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary / Q000235:genetics / Q000502:physiology; D017472:Receptors, Interleukin-1 / Q000737:chemistry / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D051197:Toll-Like Receptor 4 / Q000737:chemistry / Q000378:metabolism*; D051199:Toll-Like Receptor 7 / Q000737:chemistry / Q000378:metabolism*
chemical_list: D008562:Membrane Glycoproteins; D017472:Receptors, Interleukin-1; D051197:Toll-Like Receptor 4; D051199:Toll-Like Receptor 7; C546891:SIGIRR protein, human; C434984:TIRAP protein, human