CARD domains mediate the formation of large protein complexes through direct interactions between individual caspase recruitment domains. The domains belong to a subclass of protein motif termed the 'death fold', which comprises six to seven antiparallel alpha helices with a hydrophobic core and an outer face composed of charged residues, and which is conserved at least as far as the ced-3 and ced-4 genes in C. elegans. Other 'death fold' motifs in this class are found in the pyrin domain (PYD), death domain (DD), and death effector domain (DED). All function primarily in regulation of apoptosis and inflammatory responses.
The NACHT–leucine-rich repeat (NLR) protein, Ipaf-1 features an N-terminal CARD domain, a nucleotide-binding domain, and C-terminal leucine-rich repeats (LRRs), homologous to those found in Toll-like receptors. Ipaf-1 has a primary role in regulation of proteolytic processing of pro-IL-1β and pro-IL-18 into their mature forms by way of association in a large complex known as the inflammasome.
Ipaf-1 activation by the intracellular bacterium S. typhimurium or other stress signals, causes Ipaf-1 to recruit a CARD-containing adapter termed ASC and caspase-1. This ASC•caspase-1 complex activates caspase-1 and leads to IL-1β and IL-18 maturation.
CARD proteins also participate in recognition of intracellular dsRNA found in a number of viral genomes, including the para-, orthomyxoviridae, and rhabdoviridae. Unlike NLRs, these RIG-I and MDA5 proteins contain twin N-terminal CARD domains plus C-terminal RNA helicase domains that directly interact with and process the double-stranded viral RNA. This processing renders the CARD domains available for interaction with the CARD motif of IPS-1/MAVS/VISA/Cardif, which is a mitochondrion-anchored downstream adaptor.
Because CARD proteins function as regulators of inflammation, the constitutive activation of certain CARD proteins might play a causative role in some inflammatory syndromes.
tags [Proteins] [apoptosis] [CARD+domains] [inflammation] [Toll-like+receptor]