title: POP1 might be recruiting its type-Ia interface for NLRP3-mediated PYD-PYD interaction: Insights from MD simulation.
abstract: Inflammasomes are multiprotein caspase-activating complexes that enhance the maturation and release of proinflammatory cytokines (IL-1β and IL-18) in response to the invading pathogen and/or host-derived cellular stress. These are assembled by the sensory proteins (viz NLRC4, NLRP1, NLRP3, and AIM-2), adaptor protein (ASC), and effector molecule procaspase-1. In NLRP3-mediated inflammasome activation, ASC acts as a mediator between NLRP3 and procaspase-1 for the transmission of signals. A series of homotypic protein-protein interactions (NLRP3PYD:ASCPYDand ASCCARD:CASP1CARD) propagates the downstream signaling for the production of proinflammatory cytokines. Pyrin-only protein 1 (POP1) is known to act as the regulator of inflammasome. It modulates the ASC-mediated inflammasome assembly by interacting with pyrin domain (PYD) of ASC. However, despite similar electrostatic surface potential, the interaction of POP1 with NLRP3PYDis obscured till date. Herein, to explore the possible PYD-PYD interactions between NLRP3PYDand POP1, a combined approach of protein-protein docking and molecular dynamics simulation was adapted. The current study revealed that POP1's type-Ia interface and type-Ib interface of NLRP3PYDmight be crucial for 1:1 PYD-PYD interaction. In addition to type-I mode of interaction, we also observed type-II and type-III interaction modes in two different dynamically stable heterotrimeric complexes (POP1-NLRP3-NLRP3 and POP1-NLRP3-POP1). The inter-residual/atomic distance calculation exposed several critical residues that possibly govern the said interaction, which need further investigation. Overall, the findings of this study will shed new light on hitherto concealed molecular mechanisms underlying NLRP3-mediated inflammasome, which will have strong future therapeutic implications.
authors.affiliation: Department of Bioinformatics, Orissa University of Agriculture and Technology, Bhubaneswar, -751003, Odisha, India.
authors.forename: Jitendra
authors.identifier: 0000-0003-4628-5956
authors.initials: J
authors.lastname: Maharana
authors.affiliation: Animal Genomics Lab, Animal Biotechnology Centre, ICAR-National Dairy Research Institute, Karnal, 751003, Haryana, India.
authors.forename: Ashutosh
authors.initials: A
authors.lastname: Vats
authors.affiliation: Department of Bioinformatics, Orissa University of Agriculture and Technology, Bhubaneswar, -751003, Odisha, India.
authors.forename: Santwana
authors.initials: S
authors.lastname: Gautam
authors.affiliation: Department of Bioinformatics, Orissa University of Agriculture and Technology, Bhubaneswar, -751003, Odisha, India.
authors.forename: Bibhu Prasad
authors.initials: BP
authors.lastname: Nayak
authors.affiliation: Animal Genomics Lab, Animal Biotechnology Centre, ICAR-National Dairy Research Institute, Karnal, 751003, Haryana, India.
authors.forename: Sushil
authors.initials: S
authors.lastname: Kumar
authors.affiliation: Department of Bioinformatics, Orissa University of Agriculture and Technology, Bhubaneswar, -751003, Odisha, India.
authors.forename: Jasobanta
authors.initials: J
authors.lastname: Sendha
authors.affiliation: Animal Genomics Lab, Animal Biotechnology Centre, ICAR-National Dairy Research Institute, Karnal, 751003, Haryana, India.
authors.forename: Sachinandan
authors.initials: S
authors.lastname: De
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000737:chemistry / Q000378:metabolism*; D020170:Caspase 1 / Q000378:metabolism; D006801:Humans; D058847:Inflammasomes / Q000378:metabolism; D056004:Molecular Dynamics Simulation; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding; D012261:Ribonucleoproteins / Q000737:chemistry / Q000378:metabolism*
chemical_list: D051017:Apoptosis Regulatory Proteins; D058847:Inflammasomes; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C490350:POP1 protein, human; D012261:Ribonucleoproteins; D020170:Caspase 1
keywords: NLRP3; POP1; PYD-PYD interaction; inflammasome; molecular dynamics simulation