93
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.
