A ring-like model for ASC self-association via the CARD domain

Abstract

AbstractInflammasomes are molecular platforms controlling the innate immune response to pathogens and cellular stress. ASC is an adaptor protein common to most NLR (nucleotide-binding domain and leucine-rich repeat containing receptor) inflammasome complexes as its N-terminal PYD and C-terminal CARD interact with the homologous domains in NLR and procaspase-1. Although inflammasome activation depends on ASC oligomerization, the molecular basis of ASC self-association and the protein interactions mediating the inflammatory signaling pathway remain unknown. Both CARD and PYD domains are involved in the oligomerization process of ASC. Based on our previous structural and dynamics data on ASC we propose a model for its oligomerization consisting of a 7-member ring. In this model, CARD monomers associate via type I homotypic interactions leaving the remaining binding site of each monomer free for further oligomerization and thus ring formation. A second more open PYD ring is accommodated on top of the CARDs. Our model is discussed in light of previous work evidencing the formation of helical filaments and large globular structures by ASC. The double-ring model can help in the understanding of inflammasome assembly, nevertheless, ASC oligomerization has to be envisaged as a complex process that might include molecular organizations with structurally different features.