Models of SIGIRR inhibiting the Toll-like receptor TLR4 signaling pathway

摘要

Toll-like receptors (TLRs) belong to the Toll-like receptor (TLR)'interleukin-l receptor (IL-1R) superfamily. which is defined by a common cytoplasmic Toll interleukin-1 receptor (TIR) domain. These receptors recognize pathogen-associated molecular patterns and initiate an intracellular kinase cascade to cause an immediate defensive response. SIGIRR (single immunoglobulin interleukin-1 receptor-related molecule), another member of the TLRTL-IR superfamily. acts as a negative regulator of the MyD88-dependent TLR signaling. It attenuates the recruitment of MyD88 adaptors to the receptors with its intracellular TIR domain. Thus. SIGIRR reveals potential significance in the therapy of autoimmune diseases. However, the mechanism how SIGIRR structurally interacts with TLRs and adaptor molecules remains unclear. Here, we developed three-dimensional structures for the TIR domains of TLR4. MyD88 and SIGIRR based on computational modeling. Through protein-protein docking analysis, we suggest models of essential complexes involved in the TLR4 signaling and the SIGIRR inhibiting processes. SIGIRR may exert its inhibitory effect through blocking the molecular interface of TLR4-TLR4 and MyD88-MyD88 dimers mainly via its BB-loop region.