Intracellular signaling, molecular modeling and docking of human Dectin-1 receptor and its microbial and non-microbial ligands: a novel gateway to control inflammatory and immune diseases

Human Dectin-1 receptor, a type of pattern recognition receptor, is expressed in dendritic cells, monocytes, macrophages and a subset of T-cells. It comprises an extracellular C-type lectin domain (CTLD), transmembrane region and immunoreceptor tyrosine based activation motif (ITAM) containing cytoplasmic domain. Stimulation of CTLD by fungal β-glucans initiates various cellular pro-inflammatory and immune responses that are controlled by downstream signaling components (Syk and Src kinases and PKCδ) of Dectin-1 receptor. Using immunoblotting, FACS analysis, fluorescence microscopy and SPR technique, we confirmed Syk and Src association with Cytopalsmic Domain of Dectin-1 Receptor (CDDR) is dependent on novel down-stream signaling kinase PKCδ expression and activity that directly bind with the Tyr-15 of ITAM motif. Additionally, we have identified osteopontin (OPN) as a non-microbial endogenous ligand that signals through Dectin-1 receptor for activation of NADPH oxidase in human monocytes. It is an acidic secreted glycoprotein highly expressed by immune cells and involved in pathogenesis of atherosclerosis and vascular remodeling. To combat these pathophysiological conditions and drug designing homology model of CTLD, CDDR and OPN have been constructed using bioinformatics tools. The interaction analysis of regulatory molecular complex of Dectin-1, i.e., CDDR and PKCδ is done through protein-protein docking strategy using HADDOCK webserver. OPN and Dectin-1 interaction pattern were also predicted in addition with post translational modification sites: some myristoylation, N-glycosylation sites, tyrosine protein kinases sites and cell attachment sequence. These findings will be a milestone in control of bacterial and fungal infections and intervention of atherosclerosis.