A pyrin domain (PYD, also known as PAAD/DAPIN) is a protein domain and a subclass of protein motif known as the death fold, the 4th and most recently discovered member of the death domain superfamily (DDF). It was originally discovered in the pyrin protein, or marenostrin, encoded by MEFV. The mutation of the MEFV gene is the cause of the disease known as Familial Mediterranean Fever. The domain is encoded in 23 human proteins and at least 31 mouse genes. Proteins containing a pyrin domain are frequently involved in programmed cell death processes including pyroptosis and apoptosis. Proteins that possess a pyrin domain interact with the pyrin domains in other proteins to form of multi-protein complexes called inflammasomes and to trigger downstream immune responses. Structure Pyrin domains are a ~90 amino acid motif present only at the N-terminus of proteins. The core is made of highly conserved hydrophobic residues surrounded by five or six alpha helices with α1→2 linkages. The hydrophobic core allows self-oligomerization into punctate or speck filamentous formations. Polar residues on the surface of the domain allow the formation of the characteristic homotypic PYD-PYD interactions. Acidic residues are typically located in the α2 and α3 helices while basic residues are located on the α1 and α4 helices. Compared to other members of the DDF they contain a distinctly elongated α2-α3 loop. This loop, especially α3, is highly variable among PYDs of different proteins which allows binding specificity with other PYDs of the same type. Function Proteins containing PYD domains function as cytosolic pattern recognition receptors (PRRs) that sense danger-associated molecular patterns (DAMPs) and pathogen-associated molecular patterns (PAMPs). Homotypic interactions between PYD domains in receptor and adaptor proteins trigger downstream inflammasome formation. First, receptor proteins (such as NLRs and ALRs) are activated by their putative DAMP or PAMP ligand. These receptors undergo a conformational change exposing their PYD domain. Generally, an adaptor protein (ASC) containing both a PYD and a caspase recruitment domain (CARD) is recruited forming a PYD-PYD electrostatic interaction with the receptor's domain. More ASC-PYDs spontaneously self-oligomerize and forming a multi-protein complex called an inflammasome. Pro-caspase-1 and caspase-8 are activated through an induced proximity mechanism. Caspases can then cascade to multiple downstream pathways to trigger pyroptosis and secretion of pro-inflammatory cytokines. Types Types of proteins containing a PYD domain include an adaptor, apoptosis-associated speck-like protein containing a CARD (ASC), regulatory proteins like pyrin or pyrin-only proteins (POPs),