Insights into structure and dynamics of extracellular domain of Toll-like receptor 5 in Cirrhinus mrigala (mrigala): A molecular dynamics simulation approach.

Ajaya Kumar Rout,Rajkumar Jena,Bhaskar Behera,Bijay Kumar Behera,Budheswar Dehury,Diptimayee Maharana,Sheela Rani Udgata,Pranaya Kumar Parida,Varsha Acharya,Nagendra Kumar Kaushik

doi:10.1371/journal.pone.0245358

Abstract

The toll-like receptor 5 (TLR5) is the most conserved important pattern recognition receptors (PRRs) often stimulated by bacterial flagellins and plays a major role in the first-line defense against invading pathogenic bacteria and in immune homeostasis. Experimental crystallographic studies have shown that the extracellular domain (ECD) of TLR5 recognizes flagellin of bacteria and functions as a homodimer in model organism zebrafish. However, no structural information is available on TLR5 functionality in the major carp Cirrhinus mrigala (mrigala) and its interaction with bacterial flagellins. Therefore, the present study was undertaken to unravel the structural basis of TLR5-flagellin recognition in mrigala using structural homodimeric TLR5-flagellin complex of zebrafish as reference. Integrative structural modeling and molecular dynamics simulations were employed to explore the structural and mechanistic details of TLR5 recognition. Results from structural snapshots of MD simulation revealed that TLR5 consistently formed close interactions with the three helices of the D1 domain in flagellin on its lateral side mediated by several conserved amino acids. Results from the intermolecular contact analysis perfectly substantiate with the findings of per residue-free energy decomposition analysis. The differential recognition mediated by flagellin to TLR5 in mrigala involves charged residues at the interface of binding as compared to the zebrafish complex. Overall our results shows TLR5 of mrigala involved in innate immunity specifically recognized a conserved site on flagellin which advocates the scientific community to explore host-specific differences in receptor activation.

Highlights

The innate immune system provides a robust and efficient first line of defense against invading microbial pathogens through evolutionary conserved pattern recognition receptors (PRRs) [1]
To understand the molecular evolution of toll-like receptor 5 (TLR5) from Cirrhinus mrigala, we performed a phylogenetic analysis of Cirrhinus Mrigala TLR5 (CmTLR5) with the sequences of TLR5 from closely related organisms obtained after BLASTp search against the non-redundant database of NCBI
TLR5 plays a significant role in the innate immune system, host defense, and bacterial pathogen-associated molecular patterns (PAMPs) recognition involved in signal transduction

Summary

Introduction

The innate immune system provides a robust and efficient first line of defense against invading microbial pathogens through evolutionary conserved pattern recognition receptors (PRRs) [1]. These conserved PRRs are broadly classified into four categories viz. NOD-like receptors (NLRs), RIG-I-like receptors (RLRs), C-type lectin receptors (CLRs), and toll-like receptors (TLRs) [2]. Among these PRRs, TLRs are germline-encoded receptors which elicit defense response against invasion of pathogens, and trigger rapid inflammatory responses upon recognition of ligands. TLRs can recognize numerous ligands i.e., molecules derived from pathogens (exogenously) and processed by the host cell (endogenously)

Methods

Results

Conclusion