Abstract
The nucleotide-binding and oligomerization domain (NOD)-containing protein 1 (NOD1) plays the pivotal role in host-pathogen interface of innate immunity and triggers immune signalling pathways for the maturation and release of pro-inflammatory cytokines. Upon the recognition of iE-DAP, NOD1 self-oligomerizes in an ATP-dependent fashion and interacts with adaptor molecule receptor-interacting protein 2 (RIP2) for the propagation of innate immune signalling and initiation of pro-inflammatory immune responses. This interaction (mediated by NOD1 and RIP2) helps in transmitting the downstream signals for the activation of NF-κB signalling pathway, and has been arbitrated by respective caspase-recruitment domains (CARDs). The so-called CARD-CARD interaction still remained contradictory due to inconsistent results. Henceforth, to understand the mode and the nature of the interaction, structural bioinformatics approaches were employed. MD simulation of modelled 1:1 heterodimeric complexes revealed that the type-Ia interface of NOD1CARD and the type-Ib interface of RIP2CARD might be the suitable interfaces for the said interaction. Moreover, we perceived three dynamically stable heterotrimeric complexes with an NOD1:RIP2 ratio of 1:2 (two numbers) and 2:1. Out of which, in the first trimeric complex, a type-I NOD1-RIP2 heterodimer was found interacting with an RIP2CARD using their type-IIa and IIIa interfaces. However, in the second and third heterotrimer, we observed type-I homodimers of NOD1 and RIP2 CARDs were interacting individually with RIP2CARD and NOD1CARD (in type-II and type-III interface), respectively. Overall, this study provides structural and dynamic insights into the NOD1-RIP2 oligomer formation, which will be crucial in understanding the molecular basis of NOD1-mediated CARD-CARD interaction in higher and lower eukaryotes.
Highlights
Innate immunity plays a crucial role in host-defence mechanism against infectious pathogens, which is governed by a set of germ-line encoded receptors, called as pattern recognitionPLOS ONE | DOI:10.1371/journal.pone.0170232 January 23, 2017Computational Insights into NOD1-Mediated caspaserecruitment domains (CARDs)-CAspase Recruitment Domain (CARD) Interaction receptors (PRRs) [1]
The dynamic stability and compactness of CARDs were gauged by calculating the backbone root mean square deviation (RMSD) and radius of gyration (Rg) from the molecular dynamics (MD) trajectories
The analysis of secondary structure from MD trajectory seemed quite stable during the simulation period and a 310-helix cum turn was noticed in the α6 position of RIP2CARD (Fig 1B)
Summary
Innate immunity plays a crucial role in host-defence mechanism against infectious pathogens, which is governed by a set of germ-line encoded receptors, called as pattern recognitionPLOS ONE | DOI:10.1371/journal.pone.0170232 January 23, 2017Computational Insights into NOD1-Mediated CARD-CARD Interaction receptors (PRRs) [1]. PRRs are generally activated by invading pathogenic patterns; termed as pathogen-associated molecular patterns (PAMPs) and/or self-generated danger signals, called as damage/danger-associated molecular patterns (DAMPs) [2,3]. These PRRs are classified into five major groups on the basis of their sub-cellular location, domain architecture, structural fold, specificity to ligands and molecular function. The NLR family members show tripartite domain architecture and are characterized by the presence of central nucleotide-binding and oligomerization domain (NOD/NACHT; found in NAIP, CIITA, HET-E and TP1 proteins). In addition to NACHT, they contain one/two effector-binding domain/s [EBD: CAspase Recruitment Domain (CARD)/ PYrin Domain (PYD)] towards the N-terminal end and a varied number of Leucine Rich Repeats (LRRs) towards the C-terminal region [6,7,8]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
