In Silico Perspective into Interactions and Mutations in Human TLR4 and Ebola Glycoprotein

In Silico Perspective into Interactions and Mutations in Human TLR4 and Ebola Glycoprotein

Sujay Ray (University of Kalyani, India) and Arundhati Banerjee (National Institute of Technology, India)
DOI: 10.4018/978-1-5225-0362-0.ch008
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Abstract

Toll-Like Receptor-4 (TLR4) senses life-threatening Ebola virus Glycoprotein (GP) and produces pro-inflammatory cytokines, resulting in lethal Ebola virus infections. GP2-subunit of Ebola promotes viral entry via membrane fusion. The present study models, optimizes and demonstrates the 3D monomer of the responsible human protein. The essential residue (studied from wet-laboratory research) was observed to be functionally conserved from multiple-sequence alignment. Thus, after performing point-mutation, the mutant protein was satisfactorily re-modelled; keeping its functionality preserved. Comparable residual participation in GP2 and each of the proteins was examined, individually. Stability of the proteins and protein-GP2 complexes on mutation; were discerned via energy calculations, solvent-accessibility area and conformational switching, with supportive statistical significances. Therefore, this probe paves a pathway to examine the weaker interaction of the stable mutated human protein with Ebola GP2 protein, thereby defending the Ebola viral entry.
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Introduction

Functioning of the immune system depends greatly upon the Toll-Like Receptors (TLRs), which are distinct, membrane-spanning, non-catalytic receptors generally expressed in sentinel cells including not only dendritic cells but also macrophages. Among them, Toll-Like Receptor 4 (TLR4) protein, which is encoded by tlr4 gene (Rock et.al., 1998), senses the presence of Ebola virus glycoprotein (GP).

Initially, Ebola virus targets the monocytes and macrophages (Yong-chen, Wen-chen & Pamela, 2008). This leads to a stimulus to generate the pro-inflammatory cytokines and chemokines (Yong-chen, Wen-chen & Pamela, 2008). These inflammatory cytokines generally results further to the development of a shock in the circulatory system (Okumura, Pitha, Yashimura & Harty, 2010). This shock is thus observed in the fatal infections by Ebola virus, which has turned out to serve as world’s alarming danger (Okumura, Pitha, Yashimura & Harty, 2010). TLR4 identifies the Ebola virus glycoprotein (GP) upon particles which are specifically virus-like in nature (VLPs) (Okumura, Pitha, Yashimura & Harty, 2010). The resultant TLR4 signalling pathways further aid to release the pro-inflammatory cytokines and suppressor of cytokine signalling 1 (SOCS1) not only in a human monocytic cell line (Okumura, Pitha, Yashimura & Harty, 2010) but also in HEK293 associated TLR4/MD2 cells (Yamamoto, Sato, Hemmi et. al., 2003; Re & Strominger, 2002). This therefore, steadily and firmly expresses the TLR4/MD2 complex (Yamamoto, Sato, Hemmi et. al., 2003; Re & Strominger, 2002). Certain experimental studies involving immune-precipitation/Western blot analyses (Okumura, Pitha, Yashimura & Harty, 2010) were undergone previously in this regard to reveal that Ebola virus and GP interacts with the TIR (Toll/Interleukin-1 Receptor) domain of TLR4 and thereby excites the expression of NF-kappaB in a TLR4-dependent manner (Yamamoto, Sato, Hemmi et. al., 2003).

The Ebola glycoprotein subunit; GP0 undergoes a cleavage with the performance of a cellular protease, also known as furin convertase, into two subunits (Balaji, Jizhen, Haiqing & Lijun, 2005). One of the subunit is GP1 having approximately 130kDa, and the other one is GP2 (∼24 kDa), which resides mainly in the transmembrane. GP1 is correlated with GP2, possibly via both non-covalent interactions as well as disulfide linkages (Jeffers, Sanders & Sanchez, 2002; Volchkov, Feldmann, Volchkova & Klenk, 1998) For receptor binding purpose, the GP1 subunit serves to be responsible one (Takada et.al., 1997; Wool-Lewis & Bates, 1998). Then further cell membrane fusion of the virus and its entry is mediated by GP2 subunit (Takada et.al., 1997; Wool-Lewis & Bates, 1998).

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