title: NOD1CARD Might Be Using Multiple Interfaces for RIP2-Mediated CARD-CARD Interaction: Insights from Molecular Dynamics Simulation.
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.
authors.affiliation: Department of Bioinformatics, Orissa University of Agriculture and Technology, Bhubaneswar, Odisha, India.
authors.forename: Jitendra
authors.identifier: http://orcid.org/0000-0003-4628-5956
authors.initials: J
authors.lastname: Maharana
authors.affiliation: Department of Bioinformatics, Orissa University of Agriculture and Technology, Bhubaneswar, Odisha, India.
authors.forename: Sukanta Kumar
authors.initials: SK
authors.lastname: Pradhan
authors.affiliation: Animal Genomics Lab., Animal Biotechnology Centre, ICAR-National Dairy Research Institute, Karnal, Haryana, India.
authors.forename: Sachinandan
authors.initials: S
authors.lastname: De
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D020169:Caspases / Q000378:metabolism*; D019281:Dimerization; D006801:Humans; D006860:Hydrogen Bonding; D056004:Molecular Dynamics Simulation; D053474:Nod1 Signaling Adaptor Protein / Q000737:chemistry / Q000378:metabolism*; D053475:Receptor-Interacting Protein Serine-Threonine Kinase 2 / Q000737:chemistry / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid; D055672:Static Electricity
chemical_list: C119067:NOD1 protein, human; D053474:Nod1 Signaling Adaptor Protein; C506253:RIPK2 protein, human; D053475:Receptor-Interacting Protein Serine-Threonine Kinase 2; D020169:Caspases