Modeling of Biomolecular Systems Interactions, Dynamics, and Allostery: Bridging Experiments and Computations - September 10-14, 2014, Istanbul, Turkey

Modeling of Biomolecular Systems Interactions, Dynamics, and Allostery Poster Session I

40-POS Board 40 Structural Toll-like Receptor Pathway May Illuminate Its Roles in Inflammation and Cancer Crosstalk Emine Guven-Maiorov 1 , Attila Gursoy 1 , Ruth Nussinov 2,3 , Ozlem Keskin 1 . 1 Koc University, Istanbul, Turkey, 2 NCI Frederick, Frederick, MD, USA, 3 Tel Aviv University, Tel Aviv, Israel. Inflammation is crucial for defense against pathogens, maintain homeostasis and heal wounds. Inflammation should be strictly regulated; if not finely tuned, it can lead to oncogenesis. Toll- like receptor (TLR) pathway orchestrates both innate and adaptive immune systems with an essential role in inflammation. Although extremely useful, the classical representation of pathways in terms of nodes-and-edges is incomplete: they exhibit which proteins interact but not how. Also, atomic details of interactions elucidate which parallel pathways can co-exist, how mutations affect the protein interactions and change the cellular outcome and support malignancies. TLR pathway plays a central role in inflammation and cancer crosstalk and construction of their structural pathway provides insights on their mechanism of action in tumor microenvironment. Here, we constructed the structural TLR pathway by employing a powerful algorithm, PRISM (PRotein Interactions by Structural Matching), mapped clinically observed oncogenic mutations of the structures of key adaptor molecules in the pathway. Structural analysis revealed that parallel pathways of TLR network are mutually exclusive due to shared binding sites: TRAF6, TRAF3, and FADD – which induce pro-inflammatory cytokines, interferons and anti-inflammatory cytokine IL-10, and apoptosis, respectively – compete to bind to the overlapping interfaces on MyD88. We also found that C27* nonsense mutation on FADD protein abolishes its interaction with MyD88 and thus prevents apoptosis. If FADD can no longer occupy MyD88 binding site, TRAF6 is free to bind, allowing constitutive activation of MAPKs and production of pro-inflammatory cytokines. And this may explain how C27* mutation on FADD contributes to initiation or progression of tumor.

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