Structural analysis of mammalian toll-like receptor signaling network

Abstract

Comprehensive maps of large-scale signaling networks are attractive for researchers interested in signal transduction mechanisms because the information they give can be used as a basis for mathematical interpretations about the topological structure. The objective in this study is to analyze the comprehensive TLR signaling map, which is a crucial part of the immune system, structurally; in order to enlighten its topological structure, i.e. the properties such as robustness, and the detection of the crosstalking molecules in sub-pathways of the large system. Ultimate goal is then to identify the key molecules as potential drug targets for the infectious diseases and PKC-z is suggested for the treatment of post-infection immunity diseases such as sepsis and atherosclerosis. Network topology is investigated via the analyses based on graph theory and linear pathways. The TLR network is found to be scale-free and it has small-world properties. According to the analysis based on graph theory, in- and out-degree distributions tend to fit the power law model ( ( ) g P k » k ) with g values of 2.12 and 2.14 and R2 values of 0.96 and 0.92, respectively. The hubs for the in-degree connections are TLR2 ligand and IKK- a/IKK-b/IKK-g complex (which is also a hub for the out-degree connection), whereas the hubs for the out-degree connections are found as TIR domain, TRAF6, Rac1/GTP complex, kB site/NF-kB (p65)/NF-kB (p50)/CBP complex, and MyD88. The network and phenotype diameters of TLR signaling network are calculated as 25 and 11, respectively with a mean path length of 8.98. Due to the small-world topology of the network, it can be concluded that the TLR network is highly robust, i.e. it can take alternative actions under perturbations. The critical signaling molecules, i.e. common species participating in most of the pathways leading to the phenotypes, are found to be: the complexes of Ubc13/Uev1A/TRAF6/TAB2/TAB3/TAK1/TAB1, TLR2/TLR2 ligand and Rac1/GTP.