CARD domain

Caspase Recruitment Domain (CARD) is a protein interaction module that is found in a wide range of proteins with functions in apoptosis, inflammation, and immune system signaling. CARD domains facilitate the assembly of signaling complexes through homotypic interactions, which are interactions between the same types of domains in different proteins. This domain is crucial for the activation of caspases, which are a family of protease enzymes playing essential roles in programmed cell death and inflammation.

Structure

The CARD domain is typically composed of six or seven alpha-helices arranged in a Greek key fold. This structure allows it to interact with other CARD domains or other types of domains within signaling proteins, such as the NOD-like receptors (NLRs) and the apoptosis-associated speck-like protein containing a CARD (ASC). The specificity of these interactions is determined by the surface charge and the distribution of hydrophobic and hydrophilic residues on the CARD domain.

Function

CARD domains are primarily involved in the regulation of caspase activation, which is a critical step in the initiation of apoptosis and the processing of inflammatory cytokines. They do this by mediating the oligomerization of initiator caspases (e.g., caspase-9) in the apoptosome complex or the formation of multiprotein complexes like the inflammasome, which activates inflammatory caspases (e.g., caspase-1).

In the context of the immune system, CARD domains play a significant role in antiviral responses. Proteins containing CARD domains, such as the mitochondrial antiviral-signaling protein (MAVS), are essential for the activation of NF-κB and IRF3, transcription factors that induce the expression of type I interferons and other pro-inflammatory cytokines.

Examples of CARD Domain-Containing Proteins

- Caspase-9: An initiator caspase in the apoptosis pathway, which is activated through interaction with the CARD domain of Apaf-1 in the apoptosome. - Apaf-1: Apoptotic protease activating factor-1, which contains a CARD domain that interacts with caspase-9, leading to its activation. - MAVS: Mitochondrial antiviral-signaling protein, which uses its CARD domain to interact with RIG-I like receptors (RLRs) and initiate antiviral signaling pathways. - ASC: Apoptosis-associated speck-like protein containing a CARD, which acts as an adaptor protein in the formation of the inflammasome.

Clinical Significance

Mutations in CARD domain-containing proteins have been linked to various human diseases, including autoimmune disorders, cancer, and susceptibility to infectious diseases. For example, mutations in NOD2, a protein that contains two CARD domains, have been associated with Crohn's disease, an inflammatory bowel disease.

Understanding the molecular mechanisms of CARD domain interactions and their role in signaling pathways is crucial for the development of therapeutic strategies targeting these pathways in disease.