Abstract

The signaling response of TLR2 to ligands has always been as a homodimer or in heterodimerization with TLR1/TLR6. The Toll/Interleukin-1 Receptor (TIR) domain of the TLR cytoplasmic region regulates the dimerization and interactions with adaptor molecules to build an active signaling complex. To understand the conservation of functionality of the TLR2-heterodimers between the distantly related species human(h) and mice(m), the pattern of TIR-TIR interaction in heterodimers has been studied through the sequence-structural point of view. Comparative analysis of primary sequence and structural pattern of TLRs(1/2/6) corroborates higher sequence homology between TLR1 and TLR6. Molecular docking analysis of TLR2-TLR1 and TLR2-TLR6 cytoplasmic dimers in both mouse and human have identified that for interaction the BB loop/near-BB loop residues of TLR2 are involved with the near-DD loop of TLR1 and DD loop residues of TLR6 within the TIR domains, which may cause to differential signaling. Molecular dynamics simulation of dimers for both human and mice species recognize stable interface between near-BB/BB loop region of TLR2 and discrete near-DD and DD loop region of TLR1 and TLR6 respectively. The observed dimerization pattern in both the species is further supported by Alanine scanning mutation study. However, Solvent Accessible Surface Area (SASA) of BB and DD loop regions of the cytoplasmic monomers and the heterodimers suggests that while TLR2 BB loop is actively associated as the dimer interface with its heterodimer partners in both the species, the DD loop acts as the active interfacing region in hTLR1 and mTLR6.

Communicated by Ramaswamy H. Sarma

摘要

TLR2 对配体的信号反应一直是同源二聚体或与 TLR1/TLR6 异二聚化。TLR 细胞质区域的 Toll/Interleukin-1 受体 (TIR) 结构域调节二聚化和与衔接分子的相互作用，以构建活性信号复合物。为了了解 TLR2-异二聚体在远缘物种人类 (h) 和小鼠 (m) 之间的功能守恒，已通过序列结构的观点研究了异二聚体中 TIR-TIR 相互作用的模式。TLRs(1/2/6)的一级序列和结构模式的比较分析证实了TLR1和TLR6之间更高的序列同源性。小鼠和人类中 TLR2-TLR1 和 TLR2-TLR6 细胞质二聚体的分子对接分析已经确定，对于相互作用，TLR2 的 BB 环/近 BB 环残基与 TLR1 的近 DD 环和 TLR6 的 DD 环残基有关在 TIR 域内，这可能会导致差分信号。人和小鼠物种二聚体的分子动力学模拟分别识别 TLR2 的近 BB/BB 环区域与 TLR1 和 TLR6 的离散近 DD 和 DD 环区域之间的稳定界面。丙氨酸扫描突变研究进一步支持了在这两个物种中观察到的二聚化模式。然而，

由 Ramaswamy H. Sarma 传达