Modeling of Biomolecular Systems Interactions, Dynamics, and Allostery: Bridging Experiments and Computations - September 10-14, 2014, Istanbul, Turkey

Modeling of Biomolecular Systems Interactions, Dynamics, and Allostery Poster Session II

83-POS Board 36 Structural and Dynamics Aspects of ASC Speck Assembly Ali C. Sahillioglu 3,4 , Fidan Sümbül 1,2 , Nesrin Ozoren 3,4 , Turkan Haliloglu 1,2 . 1 Bogazici University, Istanbul, Turkey, 2 Bogazici University, Istanbul, Turkey, 3 Bogazici University, Istanbul, Turkey, 4 Bogazici University, Istanbul, Turkey. The inflammasome complexes are activated by rapid formation of ASC speck which acts as an adaptor that bridges procaspase-1 to the receptors. The resemblance between the ASC speck and aggresome raises the question whether the ASC speck formation is a result of specific interactions between PYD and CARD which both belong to the death fold superfamily or simply aggregation of hydrophobic patches of ASC proteins. To address this question, we performed structure and dynamics based analyses on the ASC protein using Gaussian Network Model (GNM) of PYD and CARD, and Molecular Dynamics (MD) simulations of the wild type and in- silico mutated PYD, with the mutational analysis on the ASC structure and its separated domains in human cells, we show that the ASC speck formation is an organized structure based on specific homophilic but not heterophilic interactions by PYD and CARD separately. PYD is able to use alternative interaction modes other than type I that might be important in compaction of the ASC speck. We propose a model in which filament formation is the first level of organization in the ASC speck and filaments further compact in a higher organization level.

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