Multiscale simulation unravel the kinetic mechanisms of inflammasome assembly

Publication date: Available online 21 November 2019Source: Biochimica et Biophysica Acta (BBA) - Molecular Cell ResearchAuthor(s): Zhaoqian Su, Yinghao WuAbstractIn 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 ASCPYD 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 fra...
Source: Biochimica et Biophysica Acta (BBA) Molecular Cell Research - Category: Molecular Biology Source Type: research