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Multiscale Simulation Unravel the Kinetic Mechanisms of Inflammasome Assembly
- Source :
- Biochim Biophys Acta Mol Cell Res
- Publication Year :
- 2019
-
Abstract
- In the innate immune system, the host defense from the invasion of external pathogens triggers the inflammatory responses. Proteins involved in the inflammatory pathways were often found to aggregate into supramolecular oligomers, called ‘inflammasome’, mostly through the homotypic interaction between their domains that belong to the death domain superfamily. Although much has been known about the formation of these helical molecular machineries, the detailed correlation between the dynamics of their assembly and the structure of each domain is still not well understood. Using the filament formed by the PYD domains of adaptor molecule ASC as a test system, we constructed a new multiscale simulation framework to study the kinetics of inflammasome assembly. We found that the filament assembly is a multi-step, but highly cooperative process. Moreover, there are three types of binding interfaces between domain subunits in the ASC(PYD) filament. The multiscale simulation results suggest that dynamics of domain assembly are rooted in the primary protein sequence which defines the energetics of molecular recognition through three binding interfaces. Interface I plays a more regulatory role than the other two in mediating both the kinetics and the thermodynamics of assembly. Finally, the efficiency of our computational framework allows us to design mutants on a systematic scale and predict their impacts on filament assembly. In summary, this is, to the best of our knowledge, the first simulation method to model the spatial-temporal process of inflammasome assembly. Our work is a useful addition to a suite of existing experimental techniques to study the functions of inflammasome in innate immune system.
- Subjects :
- Inflammasomes
Computational biology
Molecular Dynamics Simulation
Article
Domain (software engineering)
Protein filament
03 medical and health sciences
0302 clinical medicine
Molecular recognition
Protein sequencing
medicine
Humans
Molecular Biology
030304 developmental biology
Death domain
0303 health sciences
Innate immune system
Binding Sites
Chemistry
Cryoelectron Microscopy
Inflammasome
Cell Biology
Multiscale modeling
CARD Signaling Adaptor Proteins
Kinetics
Monte Carlo Method
030217 neurology & neurosurgery
Algorithms
medicine.drug
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Journal :
- Biochim Biophys Acta Mol Cell Res
- Accession number :
- edsair.doi.dedup.....505678c4836179d4185ff12af6328d87